Gas delivery method and apparatus

ABSTRACT

An apparatus, method and system for delivering CO 2  into an inspiratory gas stream to formulate a blended respiratory gas in a manner that continuously maintains a target CO 2  concentration in a volume of the inspired respiratory gas, for example, over the course of a breath or a volumetrically definable part thereof or a series of partial or full breaths.

FIELD OF THE INVENTION

The present invention relates to a device, method and system fordelivering CO₂ into an inspiratory gas stream to formulate a blendedrespiratory gas in a manner that continuously maintains a target CO₂concentration in a volume of the inspired respiratory gas, for example,over the course of a breath or a volumetrically definable part thereofor a series of partial or full breaths.

BACKGROUND OF THE INVENTION

The arterial partial pressure of CO₂ (PaCO₂) is intimately related tothe acid base status of the blood. CO₂ combines with water to formcarbonic acid. The higher the PaCO₂ the more acid is the blood. CO₂ isformed in the body by metabolism and is eliminated from the lungs byventilation. The relationship between PCO₂ and ventilation is arectangular hyperbola with PCO₂ becoming infinite at low ventilationsand reaching an asymptote of 0 at infinite ventilation. Ventilation istherefore controlled in response to chemosensitive neurons located inthe brainstem and surrounding major arteries.

There are many occasions where it is required to induce a change inPaCO₂ in a subject or patient. One example is to study the responses ofvarious body systems to changes in CO₂ such as the chemoreceptor cellsthemselves, breathing pattern, arousal, brain blood flow, coronaryartery blood flow, ocular blood flow, renal blood flow, changes in bloodvessel diameter in various organs and major arteries such as thebrachial artery, and changes in brain waves, behavior and seizurethreshold. We pick brain blood flow, blood volume and oxygen extractionfraction as an example for the use of changes in PaCO₂. For examplebrain blood flow can be measured by various modalities that includetrans-cranial Doppler, positron emission tomography (PET) and singleproton emission tomography (SPECT), and nuclear magnetic resonanceimaging (MRI) techniques such as blood oxygen level dependent (BOLD) andarterial spin labeling (ASL) echo. CO₂ is used as the provocativestimulus to induce a change in blood flow and thus measure the vascularreactivity. Traditional methods have assumed that infusing CO₂ into amask will change the PaCO₂. Infusing the CO₂ into the mask changes theexhaled PCO₂ but this is unreliably related to the PaCO₂, the actualphysiological stimulus at the site of action. It has been shown byPrisman et al¹. and Hoskins et al.² that this is totally ineffective(see discussion in Prisman¹ and Mark et al.^(3,4)). Still, infusion ofCO₂ into a mask or fixing the inspired PCO₂ is nevertheless still usedfor studying brain vascular reactivity. With this method, one can detecta change in brain blood flow but because one doesn't know the PaCO₂, theactual reactivity is unknown. For example, a small change in the measureof blood flow may be due to low reactivity or small change in PaCO₂.

An improved method of implementing changes in PaCO₂ has been presentedby Prisman et al.¹. The theory presented by Slessarev et al.⁵ is thatsequential gas delivery provides good reliability in targeting a changein PaCO₂. The theory of such targeting requires the delivery of a firstgas which has a predetermined concentration of oxygen and CO₂ to affecta PaCO₂ at the first part of the breath and the remainder of the breathconsists of a second gas which has CO₂ concentration equal to the targetPaCO₂. Ito et al.⁶ applied such a circuit to spontaneously breathinghumans and found that targeting with this system the expired partialpressure of CO₂ was substantially equal to PaCO₂ within about 2 mmHg.This is sufficiently accurate for most, but not all purposes. Forexample, calibration of MRI BOLD signals to measure oxygen consumptionof the brain require as accurate determination of PaCO₂ as can beobtained, and small discrepancies reduce the value of the calibration(Mark et al.). One source of error with the sequential gas deliverycircuit is that some first gas continues to flow and be inhaled duringthe second gas delivery phase where it is desired that only second gasbe inhaled. This is a limitation of all sequential gas deliverycircuits. A variety of active or passive valves to prevent the first gasdelivery during the phase where only second gas delivery is desired makethe system more cumbersome, uncomfortable for the subject, and moreexpensive.

SUMMARY OF THE INVENTION

According to one aspect, the present invention is directed to a methodof preparing a carbon dioxide (CO₂)-containing gas (G_(n)) that isorganized for delivery in tandem with a second gas (G₀), in manner thatcomposes a respiratory gas (G_(R)) and maintains a target CO₂concentration (FCO₂ ^(T)) in a cumulative volume of the G_(R) ofinterest (CVG_(R) ^(I)), the method comprising:

for each successive time point of interest in a growing time periodcomprising all time points of current interest T₁ to T_(last), eachsuccessive time point in turn a T_(last):

(a) obtaining input comprising or sufficient to compute:

-   -   (i) a cumulative volume of G_(R) (CVG_(R)) organized for        delivery as of T_(last) over all time points of current interest        T₁ to T_(last); and    -   (ii) a cumulative volume of CO₂ (CVCO₂) organized to compose        part of the CVG_(R) as of T_(last) in all time points of current        interest T₁ to T_(last);

(b) using the input obtained to compute a respective incremental volumeof G_(n) that must be delivered as of T_(last) so that the cumulativevolume of CO₂ in the CVG_(R) equals FCO₂ ^(T); and

(c) controlling a gas delivery means (GD_(n)) so that the respectiveincremental volume of G_(n) targets FCO₂ ^(T).

As of each successive time point of interest T_(last) (for conveniencealso called T_(current)), in a time period of interest, the CVG_(R) isunderstood to comprise all incremental volumes of G₀ organized fordelivery as of T_(last) (which cumulatively make up, as of eachsuccessive T_(last), a new CVG₀ for the respective incremented timeperiod of last interest comprising the time points T₁ to last T_(last))and all incremental volumes of G_(n) organized for delivery as ofT_(last) (which cumulatively make up, as of each successive T_(last), anew CVG_(n) for the respective incremented time period of last interestcomprising the time points T₁ to last T_(last)). As described below,consonant with one suitable placement of the sensors used to track theactual incremental volumes of gas organized for delivery, input ofCVG_(R) for the last incremented time period may be simply obtained byadding the respective CVG_(n) and CVG₀ values for this time period(sensor placement is organized to track incremental volumes of G₀ andG_(n) as of each T_(last) which are then incremented to obtain newvalues of CVG_(n) and CVG₀ for each successive time point).Alternatively, input of the CVG_(R) may be obtained by using a sensor todirectly track incremental volumes of G_(R) organized for delivery. Asexplained below, tracking respective CVG_(n) and CVG₀ values for eachT_(last) may in some instances be sufficient to compute a respectiveincremental volume of G_(n) that must be delivered as of T_(last) sothat the cumulative volume of CO₂ in the CVG_(R) equals FCO₂ ^(T) (e.g.without directly computing a respective CVCO₂ value for each time pointof interest). Various embodiments of the invention described hereafterrefer to obtaining input of alternative cumulative volume terms neededfor computing a respective incremental volume of G_(n) that must bedelivered so that the cumulative volume of CO₂ in the CVG_(R) equalsFCO₂ ^(T).

The expression “of interest” with reference to time points of interest,is to be understood to encompass time points that simply correspond toevents that mark the beginning or end of a period of gas delivery (e.g.for a certain number of breaths, planned or arbitrarily terminated, orcompletion of a treatment or completion of a contemporaneous medicalprocedure or diagnostic test) but could also mean “directly” of interestinsofar as the time span of making G_(R) available for breathing beginsand ends at specified points in time, whether predetermined or simplyarbitrary. It will be appreciated that computation of an error signaland related control of a gas delivery device is done at selected timeincrements (e.g. every “x” milliseconds) which implies, that within atime span of interest, time points corresponding to those increments areinherently of interest. Since time points of interest are generally timepoints used to compute e_(n), contiguous time points of interest areconsidered to be adjacent time points defining intervals of interest forcomputation of e_(n). Similarly, a volume or cumulative volume ofinterest may be of interest simply in the sense that it defines one or aseries of successive cumulated volumes that define reference volumes forcalculation of an error signal.

By computing and controlling the delivery of an incremental correctivevolume of G_(n) that must be added to combined volume of the CVG_(n) andCVG₀ (the CVG_(R)) to target the FCO₂ ^(T) as of each successive timepoint T_(last), the G_(n) is understood to be functionally organized fordelivery in tandem with the G₀.

In one preferred embodiment of the invention, each incremental volume ofgas organized for delivery by a gas delivery means (GD_(n)) may beflowed to a patient, for example via an output port which leadsunimpededly to a patient airway interface (e.g a mask) or a volume ofgas that a patient is free or forced to intake (closely followingrelease by the GD_(n)). In this connection, it is convenient to speak ofincremental volumes, of defined magnitude determined by a sensor,‘delivered’ (i.e. released for delivery) by a GDn (as well asincremented cumulative gas volumes based on these incremental volumevalues), as ‘delivered’ volumes. The phraseology ‘actually delivered’may be also be used (with the same intended meaning) for emphasis.

The term “blending” may be used to describe the act of organizingdelivery of G_(n) in tandem with the G₀ and hence the term blendingoptionally encompasses physical blending and coordinated release ofcomponents of the G_(R) to a patient.

According to another aspect, the present invention is directed to amethod of using a respiratory gas delivery system having one or more gasoutput ports to coordinate the output of a carbon dioxide(CO₂)-containing gas (G_(n)) and a second gas (G₀), in a manner thatcomposes a respiratory gas G_(R), the method comprising:

for respective time points in a series of time points of interest:

-   -   a) obtaining input of a cumulative volume of G₀ (CVG₀) or G_(R)        (CVG_(R)) delivered to a gas output port over a period        comprising the series of time points of interest;    -   b) obtaining input of a cumulative volume of G_(n) (CVG_(n)) or        CO₂ (CVCO₂) delivered to a gas output port over a period        comprising the series of time points of interest;    -   c) using the input obtained to compute an incremental volume of        G_(n) that must be delivered to an output port in tandem with        the delivered G₀ so that the cumulative volume of CO₂ in a        volume of the respiratory gas of interest (CVG_(R) ^(I)) equals        a target CO₂ concentration (FCO₂ ^(T)); and optionally    -   d) controlling a gas delivery means (GD_(n)) so that respective        incremental volumes of G_(n) delivered to an output port target        FCO₂ ^(T).

The term “equals” as used herein preferably connotes mathematicalequality but more broadly connotes a functional approximation of FCO₂^(T) based on computation of a corrective volume of CO₂ in circumstanceswhere such computation relies on inputs of incremented cumulativevolumes G₀ and/or G_(R) and G_(n) and/or CO₂ i.e. such data is used as abasis upon which to compute, at respective time points of interest, avolumetric correction factor used to deliver an incremental amount ofG_(n) to adjust the cumulative amount of G_(n) in a cumulative volume ofG_(R) of interest so that the cumulative amount of CO₂ is adjusted to atleast functionally achieve a FCO₂ ^(T). The term “target” in the samevein, broadly connotes the use any suitable control signal thatimplement the computation in step c) to deliver a corrective incrementalvolume of G_(n).

The phrase “obtaining input” is meant to be broadly construed asencompassing any form of obtaining input that allows the input to beused. For example, a processor, optionally, in the form amicroprocessor, may be programmed to receive a signal or data, forexample a signal generated by a sensor or user input, or perform acomputation using, for example, the aforementioned input, in order togenerate the particular inputs required to compute an error signal, andultimately, a control signal to a gas delivery device GDn.

Optionally, CVG_(R) ^(I) is equated to CVG_(R). Optionally, CVG_(R) ^(I)consists of (is equated to) or comprises the CVG_(R) for example the sumof CVG_(R) and an incremental volume of G_(R) that is designated to bedelivered based on an adding a corrective incremental amount of G_(n) toan incremental volume of G₀ predicted to be delivered to an output portin an ensuing time point for which sensor data is not available(optionally relying on actual data for relevant time points, optionallyone more or more immediately preceding time points). The CVG_(R) ^(I)may consist of, comprise or otherwise takes into account the CVG_(R) (asa base principle, taking CVG_(R) into account enables computation of acorrective volume of G_(n) based on volumes of gases actually madeavailable for delivery). Therefore, CVG_(R) ^(I) is preferably aselected function of CVG_(R), optionally a function which adds one ormore defined incremental volumes to the CVG_(R) as exemplified herein.The invention also contemplates a function in which a defined volume issubtracted from CVG_(R), for example as another form of correctivemeasure, for example for adjusting the inspired “dose” of carbondioxide.

Optionally, a CVG_(R) is available for immediate inspiration (i.e.following commencement of G_(n) delivery by GD_(n) to an output port)and FCO₂ ^(T) is attained within a cumulative G_(R) inspiratory volumeof no greater than 50 litres, optionally no greater than 10 litres,optionally no greater than 5 litres, optionally no greater than oneliter optionally no greater than 500 ml, optionally within a cumulativeG_(R) inspiratory volume of no greater than 100 ml, optionally within acumulative G_(R) inspiratory volume of no greater than an average humanadult or infant breath, optionally within a cumulative G_(R) inspiratoryvolume of 25 mls, optionally within a time span of a single averageinspiration, optionally within in a time span of 1 to 3 seconds.Optionally, the FCO₂ ^(T) is continuously maintained after being afterbeing attained.

The phrase “in tandem” means at least coordination in a volumetric senseto achieve proportioned output of G_(n) that matches output of G₀.However, the output of the respective components of a respiratory gasG_(R) in a respiratory gas delivery system may typically be needed orpotentially needed in an immediate sense (in real time), for example,where the output flows in real time to a patient airway interface suchas a mask or endotracheal tube or to one more gas reservoirs thecontents of which may (either immediately, imminently or as needed) bedrawn on or delivered breath by breath. The present invention notablyenables such coordination to be scaled from both a time and volumetricstandpoint to at least within a human (adult or infant) breath so thatthe volume of pure CO₂ in the CVG_(R) ^(I) (where CVG_(R) ^(I) is abreath or a partial breath of minimum size e.g. 10-25 ml., having regardto the volume/precision specifications of the GD_(n) and othercomponents) equals FCO₂ ^(T).

The term output port with reference to delivery of G_(n) broadly meansany port or junction downstream of a gas delivery means (GD_(n)),through which the volumetric output of G_(n) is controlled as describedbelow so that actual respective volumes of G_(n) delivered downstream ofthe GD_(n) target FCO₂ ^(T). Because incremented amounts of G₀ aredirectly or indirectly part of the input of a control system, optionallyembodied in a computer, the incremental amounts G_(n) for respectivetime points are effectively delivered in tandem with delivery of the G₀(delivery may result in release of G₀ to a patient in real time oroptionally take the form of volumetrically controlled accumulation ofthe G₀ e.g. if a combined gas or respective individual gases areaccumulated for delivery). As described below the invention contemplatesthe use of a control system to set a target FCO₂ ^(T), to obtain inputsof the requisite cumulative volumes of G₀ (CVG₀) or G_(R) (CVG_(R)) overa period comprising the series of time points of interest, to obtaininput of a cumulative volume of G_(n) (CVG_(n)) or CO₂ (CVCO₂) over aperiod comprising the series of time points of interest, to compute ancorrective amount incremental amount of G_(n) needed to target FCO₂ ^(T)(e_(n)) for those respective time points, to control the gas deliverymeans (e.g. a valve) in order to increment the delivered amount of G_(n)so as to target FCO₂ ^(T) and where required (e.g.) where theconcentration of CO2 in the G_(n) and optionally G₀ is not fixed toreceive input of sensors that detect concentration of gases and computean e_(n) accordingly. As described below this control system may bevariously embodied in one or more hardware components in a manner wellknown in the art.

According to one embodiment of the invention, a respiratory gas deliverysystem may comprise a conventional ventilator, anesthetic machine orother respiratory gas delivery device (machine or manually operated)having an output port for the G₀ (leading, optionally unimpeded, to a G₀containing reservoir or a patient airway interface) which is operativelycoupled to a separate G_(n) delivery device having an output portdirectly into the G₀ (for example into a G₀ delivery conduit) or into acommon volume (e.g. a patient airway interface, reservoir, manifold,connector) or different volumes which are organized to be deliveredproportionately for maintaining FCO₂ ^(T) and preferablycontemporaneously and in real time (i.e. resulting in the targetedconcentration of CO₂ in a volume of the G_(R) to be maintained (after aninitial ramp up time) continuously. The cooperation among two deviceshaving respective individual output ports or a common output port fromthe standpoint of eventual output to the patient may be understood to bea retrofit or of a priori design, The invention also contemplates arespiratory gas delivery system in the which a G₀ delivery system andG_(n) delivery system are integrated in a common unit.

Optionally, as described below, at successive time points within aseries of time points of interest, an error term as hereafter described,may be computed.

As elaborated below, a key nature of the respective time points ofinterest are those for which there are available inputs of incrementedcumulative volumes G₀ and/or G_(R) and G_(n) and/or CO₂. These inputsmay be derived from sensors that generate the signals required to obtaininput of the incremented cumulative volumes of gases delivered to anoutput port. In this manner the requisite input is obtained forcomputing, at respective time points, an incremental volume of G_(n)that must be delivered to an output port in tandem with the delivered G₀so that the cumulative volume of CO₂ in the CVG_(R) ^(I) equals FCO₂^(T). Accordingly, the series of time points of interest for whichrespective cumulative volumes of gases are obtained and computations ofan error term, as described below, are made, are understood to minimallyaccord at least with a particular application for which the respiratorygas delivery system is used i.e. requisite degree of precision forproportionally matching G_(n) and G₀ at least volumetrically and tomatch the requisite contemporaneous nature of the coordination in termsof ensuring the fraction and/or size and/or number of the breath(s) forwhich a CO₂ adjusted composition of a CVG_(R) ^(I) is sought to beachieved is timely attained and maintained. Accordingly, the respectivetime points of interest for which respective incremented volumetricinputs (CVG₀ and/or CVG_(R) and CVG_(n) and/or CVCO₂) to compute anerror term is obtained, must at least closely correspond to one anotherand to the time points for which sensor data input is obtained.

Optionally, as described below, at successive time points within aseries of time points of interest an error term may be computed.Optionally, this series of time points of interest may be described asthe most current continuous period of interest for which the targetedCO₂ concentration in a cumulative volume of G_(R) of interest ismaintained. The invention contemplates that the actual delivery of thisCVG_(R) ^(I) to the patient may lag in time. Therefore, T_(current) isnot necessarily a T_(now) in the sense of according with a currentdevice clock time/volume sensor reading. Nevertheless, each successivetime point is preferably a time point of interest at least in the sensein which it corresponds to one of the respective time points for whichincremented cumulative volumes required for computation of e_(n) isused. Each respective time point in a series of interest can beunderstood to become, in turn, a current time point T_(current)(optionally a T_(now)) at which the delivered volumes of G_(n), G₀, andCO₂ are updated based on sensor readings and these updated values can beused at each respective time point of interest for computing an errorterm e_(n). The error term e_(n) is optionally equated to a volume ofG_(n) that must be delivered so that the volume of pure CO₂ in thecombined volumes of CVG_(n), CVG₀, and e_(n) equals FCO₂ ^(T). The errorterm is converted by a controller (VC_(n)) into a signal that isdelivered to a GD_(n) so that an incremental volume of G_(n) isdelivered by the GD_(n) to target a CO₂-concentration of FCO₂ ^(T) inthe incremented volumes of CVG_(n) and CVG₀. Optionally, the VC_(n)takes the form of a PI controller. Optionally, the VC_(n) takes the formof any controller known to those skilled in the art that can acceptinput of e_(n) and compute a signal for GD_(n) to deliver an incrementalvolume of G_(n), to target FCO₂ ^(T). The output to the GD_(n) for arespective T_(current) may be generated from a weighted sum of e_(n) forthe respective T_(now), the integral of e_(n) over a time period T₁ . .. T_(current), and the derivative of e_(n) for the respectiveT_(current).

According to another aspect, the present invention is directed to adevice for coordinating the output of a carbon dioxide (CO₂)-containinggas (G_(n)) and a second gas (G₀), in a manner that composes arespiratory gas G_(R), the device comprising:

-   -   a) a control system for delivery of incremental amounts of G_(n)        in tandem with the G₀ at successive time points in a series of        time points of interest, wherein the respective incremental        amounts of G_(n) are selected to attain a target CO₂        concentration (FCO₂ ^(T)) in a cumulative volume of the G_(R)        (CVG_(R)); and    -   b) a gas delivery means (GD_(n)) for delivering the respective        incremental volumes of G_(n) to a G₀ channeling means;        the control system comprising means for obtaining input of a        cumulative volume of G₀ (CVG₀) or G_(R) (CVG_(R)) delivered to a        G₀ channeling means; means for obtaining input of a cumulative        volume of G_(n) (CVG_(n)) or CO₂ (CVCO₂) delivered by the GD_(n)        over a period comprising the series of time points of interest,        means for using the input obtained to compute an incremental        volume of G_(n) that must be delivered to the G_(n) channeling        means in tandem with the G₀ so that the cumulative volume of CO₂        in CVG_(R) equals FCO₂ ^(T); and means for controlling the        GD_(n) so that respective incremental volumes of delivered to        the G_(n) channeling means target FCO₂ ^(T). Optionally, the        device comprises a volume sensor for obtaining input of a        cumulative volume of G_(n) (CVG_(n)) or CO₂ (CVCO₂) delivered by        the GD_(n). Optionally, the device comprises input means for        setting the FCO₂ ^(T). Optionally, the control system is        implemented by a processor in the form of a computer as broadly        defined herein. The processor is optionally embodied in an IC        chip. The term “configured” when used in relation to a computer        is non-limiting in the sense that any one or more its functions        may be accomplished by a computer program product or via a        memory of any type or hard-wired into a dedicated circuit or        implemented via electronic components (consonant with the        broadest definition of the term computer used herein).

The present invention is directed to a method of delivering to a subjecta carbon dioxide (CO₂)-containing gas (G_(n)) and a second gas (G₀), ina manner that composes a respiratory gas G_(R), the method comprising:

-   -   for respective time points in a series of time points of        interest:    -   a) obtaining input of a cumulative volume of G₀ (CVG₀) or G_(R)        (CVG_(R)) delivered to a subject over a period comprising the        series of time points of interest;    -   b) obtaining input of a cumulative volume of G_(n) (CVG_(n)) or        CO₂ (CVCO₂) delivered to a subject over a period comprising the        series of time points of interest;    -   c) using the input obtained to compute an incremental volume of        G_(n) that must be delivered to the subject in tandem with the        delivered G₀ so that the cumulative volume of CO₂ in a volume of        the respiratory gas of interest (CVG_(R) ^(I)) equals a target        CO₂ concentration (FCO₂ ^(T)); and optionally    -   d) controlling a gas delivery means (GD_(n)) so that respective        incremental volumes of G_(n) delivered to the subject target        FCO₂ ^(T).

The present invention is also directed to a method of blending a carbondioxide (CO₂)-containing gas (G_(n)) and a second gas (G₀), in a mannerthat composes a respiratory gas G_(R) for delivery to a subject, themethod comprising:

-   -   for respective time points in a series of time points of        interest:    -   a) obtaining input of a cumulative volume of G₀ (CVG₀) or G_(R)        (CVG_(R)) designated for delivery to a subject over a period        comprising the series of time points of interest;    -   b) obtaining input of a cumulative volume of G_(n) (CVG_(n)) or        CO₂ (CVCO₂) designated for delivery to a subject over a period        comprising the series of time points of interest;    -   c) using the input obtained to compute an incremental volume of        G_(n) that must be designated for delivery to a subject in        tandem with the delivered G₀ so that the cumulative volume of        CO₂ in a volume of the respiratory gas of interest (CVG_(R)        ^(I)) equals a target CO₂ concentration (FCO₂ ^(T)); and    -   d) optionally controlling a gas delivery means (GD_(n)) so that        respective incremental volumes of G_(n) delivered to the subject        target FCO₂ ^(T).

In another aspect, the present invention is also directed to anintegrated circuit (IC) chip configured for carrying out a method asdescribed herein.

In another aspect, the present invention is also directed to a computerprogram product comprising a non-transitory computer readable mediumencoded with program code for controlling operation of an electronicdevice, the program code including code for computing an error terme_(n) corresponding to the incremental volume of G_(n) computed for therespective time points of interest. Optionally, the program codeincludes code for computing or obtaining input of a set of parameterscomprising CVG_(R) and CVCO2. Optionally, the program code includes codefor controlling a gas delivery means (GD_(n)) so that respectivedelivered incremental volumes of G_(n) target FCO₂ ^(T).

In another aspect, the present invention is also directed to devicecomprising an integrated circuit chip configured for carrying out themethod, for example a printed circuit board (comprising discreteelectronic components). The device optionally includes at least one gasdelivery means and optionally at least one volume sensor as hereinafterdefined. The device optionally includes an input device for inputtingFCO₂ ^(T). Optionally, FCO₂ ^(T) can be input via a variety of meansincluding, but not limited to, a keyboard, mouse, dial, knob, touchscreen, button, or set of buttons. Optionally, the target FCO₂ ^(T) canbe changed at any time.

The device optionally includes at least one CO₂ containing gas deliveryconduit.

In one embodiment, the present invention is directed to a method foradding at least one carbon dioxide-containing gas (G_(n)) to aninspiratory gas (G₀), to formulate a respiratory gas (G_(R)) fordelivery to a subject, and to maintain a targeted concentration ofcarbon dioxide (FCO₂ ^(T)) in a volume of the G_(R) of interest (CVG_(R)^(I)), comprising:

-   -   for each of a group of respective time points of interest        comprising    -   T₁ . . . T_(current) each in turn a respective T_(current):    -   (A) obtaining input of a cumulative volume of G_(n) (CVG_(n)) or        CO₂ (CVCO₂) actually delivered over all time points T₁ . . .        T_(current);    -   (B) obtaining input of a cumulative volume of G₀ (CVG₀) or G_(R)        (CVG_(R)) actually delivered over all time points T₁ . . .        T_(current);    -   (C) computing the incremental volume of G_(n) that must be        delivered to the subject so that the cumulative volume of CO₂ in        the CVG_(R) ^(I) equals FCO₂ ^(T);    -   (D) controlling a gas delivery means (GD_(n)) so that the        delivered incremental volume of G_(n) targets FCO₂ ^(T).

In one embodiment, an error term (e_(n)) is computed that represents theincremental volume of G_(n) that must be delivered to the subject sothat the cumulative volume of CO₂ in the CVG_(R) ^(I) (e.g. the actualCVG_(R)) equals FCO₂ ^(T).

Therefore, according to one embodiment, the invention is directed to amethod of adding at least one carbon dioxide (CO₂) containing gas(G_(n)) to an inspiratory gas G₀, to formulate a respiratory gas (G_(R))for delivery to a subject, and to maintain a targeted concentration ofCO₂ in a volume of the G_(R), comprising:

for each of a group of respective time points of interest T₁ . . .T_(current) each in turn a respective T_(current):

-   -   (A) obtaining input of a cumulative volume of CO₂ (CVCO₂)        actually delivered (optionally determined, based on sensor        readings, as a volume of CO₂ incremented at successive        respective time points T₁ . . . T_(current));    -   (B) obtaining input of a cumulative volume of G₀ (CVG₀) or G_(R)        (CVG_(R)) actually delivered (optionally determined, based on        sensor readings, as volumes of G₀ or G_(R) incremented at        successive respective time points T₁ . . . T_(current));    -   (C) based on an ascertained concentration of CO₂ in G_(n),        computing an error term (e_(n)) equal to the volume of G_(n)        that must be delivered so that the cumulative volume of CO₂ in        CVG_(R) equals a desired fraction FCO₂ ^(T);    -   (D) controlling a gas delivery means GD_(n) so that the actual        incremental volume of CO₂ delivered as part of the CVG_(R)        targets FCO₂ ^(T).

In one embodiment, a suitable controller (e.g. a PI or PID controller)is used to control the gas delivery means (GD_(n)) so that the deliveredincremental volume of G_(n) targets FCO₂ ^(T).

The term “fraction” and “concentration” are generally usedinterchangeably herein based on the understanding that a particularchoice of algorithm and units (if any) for expressing concentration mayvary based on whether partial pressures, fractional concentrations orpercentages are used for expressing a target concentration of CO₂ in avolume of G_(R). The abbreviations FCO₂ ^(T) and CO₂ ^(T) are also usedinterchangeably.

The term “respiratory gas” means a group of at two component gases thatare suitable for inhalation by a subject individually or at least whencombined and that meet a criterion with respect the concentration ofcarbon dioxide in any combined volume of the group of component gases.Accordingly, in a clinical setting where any particular combined volumeof the component gases is inhaled over a particular time period by asubject, as a single stream of combined component gases or multiplestreams in parallel, the FCO₂ ^(T) with respect to a cumulative volumeof G_(R) inhaled by the subject over a period of interest (e.g. a singlebreath) will have been maintained.

The actual cumulative volume of G_(R) (referred to as CVG_(R)) isunderstood to include, as preferred, the incremental volume of G_(n)that must be delivered to the subject so that the cumulative volume ofCO₂ in the CVG_(R) ^(I) equals FCO₂ ^(T).

As described above, in one embodiment of the invention the CVG_(R) ^(I)is equated to the CVG_(R). In one embodiment of the invention describedbelow, at a respective T_(current), an assumption is made about how muchinspiratory gas G₀ (the G₀ is alternately referred to as a second gas,the G_(n) alternately being referred to as a first gas) will bedelivered between T_(current) and an ensuing time point. Accordingly, inaddition to computing the incremental volume of G_(n) that must bedelivered so that the cumulative volume of CO₂ in the CVG_(R) equalsFCO₂ ^(T) it may expedient to compute at T_(current), the G_(n) thatwould be need to be delivered to target the FCO₂ ^(T) within aparticular assumed incremental amount of G₀.

In the latter connection, CVG_(R)' may optionally be computed as the sumof the CVG_(R), the assumed incremental volume of G₀ and the incrementalvolume of G_(n) that would be sought to be delivered to target the FCO₂^(T) within that incremental amount of G₀. The computation of CVG_(R)^(I) may serve other purposes as well and hence computation of CVG_(R)^(I) (however approached) is understood to preferably be a function ofan actual CVG_(R) value, for a respective T_(current), whereby one canconsequently compute the incremental volume of G_(n) that must bedelivered so that the cumulative volume of CO₂ in a particularcumulative volume of G_(R) (i.e. taking into account a CVG_(R) value)equals FCO₂ ^(T).

Obtaining input of CVG_(n) is expressed as an alternative to obtaininginput of CVCO₂. In most cases, using CVCO₂ as an input for computationof e_(n) will be preferable (optionally as an incremented volume of CO₂,incremented at each successive T_(current) within a series of timepoints of interest) as this approach best serves (in the broadest rangeof circumstances) the computational purpose of continuously tracking theincremental volume of pure CO₂ that must be delivered to target FCO₂^(T) having regard to the incremented cumulative volume of pure CO₂contributing to the incremented cumulative volume of G_(R). Obtaininginput of CVG_(n) incidental to the goal of computing the error terme_(n) may be understood to be practical as an input parameter, in aphysical sense (from volume sensor readings), and beyond that trackingCVG_(n) computationally may in theory be adequate (e.g where the G₀ isdevoid of CO₂ and the concentration of CO₂ in G_(n) is fixed) as asurrogate method of tracking CVCO₂. However, in most instances, usingCVG_(n) as a plausible alternative input parameter for computing theerror term e_(n) (e.g. especially where it must be matched with achanging value of a variable concentration of CO₂ in G_(n)—andoptionally also a fixed or changing value of a variable concentration ofCO₂ in G₀—applicable to each respective T_(current)) may becomputationally unwieldy. Therefore, optionally, determining acumulative volume of pure CO₂ (CVCO₂) delivered in a particular timeinterval, for example, a period of interest T₁-T_(current), may servethe purpose of computing e_(n) most universally and efficiently byaccommodating input of a value for the concentration of CO₂ in G_(n)(this value may 100% or less than 100%) and a value for theconcentration of CO₂ in G₀ (as this value may be 0% or more than 0%).This may be done by incrementing the volume of CO₂ from the lastT_(current) by the incremental volume of G₀ and G_(n) delivered sincethe last T_(current) weighted by their concentrations of CO₂. Thereforeit will be appreciated that even though obtaining input of both CVCO₂and CVG_(R) for each respective time of interest is the most universallypragmatic way of computing the corrective volume of G_(n) that must beadded to the cumulative volume of G_(R) as of each time point ofinterest, in some instances, as explained above, the input sufficient tocompute this corrective volume may be geared to alternativemathematically equivalent terms and algorithms. Hence, it will beappreciated that certain alternative combinations of inputs are to beviewed as particular embodiments falling within a broader range ofalternatives, namely inputs sufficient to compute CVCO₂ and CVG_(R)(i.e. algorithms using surrogate cumulative volume terms and any otherinput values such as CO₂ concentrations in G_(n) and G₀ would invariablyuse a combination of inputs sufficient to compute both CVCO₂ (acumulative volume of the pure component of interest) and CVG_(R))

As elaborated below, each successive time point within a period ofinterest becomes a current time point T_(current) at which thecumulative volumes of pure CO₂ and/or G_(n) and, G₀ and/or G_(R), areupdated based on sensor readings (which may output actual incrementalvolumes of the respective gases at each respective T_(current)) andthese updated values can be used for computing the error term e_(n). Theerror term is a volume of G_(n) computed at successive time pointsT_(current) that is converted by a controller into a signal delivered tothe GD_(n) to target (having regard to the limitations of the hardware)the desired concentration of carbon dioxide that is input or preset (CO₂^(T)). Thus the GD_(n) is signaled to deliver a corrective volume ofgas. Expressed in terms of time points identified herein, the correctivevolume may optionally be considered to be delivered during the timeinterval beginning at the respective T_(current) and optionally endingat T_(current+), optionally the immediately next ensuing T_(current+1).The term “gas delivery means”, abbreviated GD_(n) and alternatively toas a “gas delivery device” refers to specifically to hardware fordelivering (e.g. releasing, where the source gas is under pressure)specific volumes of G_(n) into the respiratory gas inspired by thepatient, preferably a device that is adapted to introduce volumes ofvariable incremental size into the respiratory gas, for example directlyinto a G_(n) carrying conduit, optionally into an inert conduit (inertvis-à-vis the composition of the G_(n)), optionally a conduit that feedsdirectly into a conduit carrying the G₀ stream such as an inspiratorylimb of a breathing circuit. The gas delivery means may be any known gasdelivery device such as a gas injector, or a valve, for example, aproportional flow control valve.

The term “pure CO₂” is used broadly to facilitate defining a fraction ofa volume of delivered CO₂ containing gas (theoretically pure CO₂) thatallows one to compute e_(n) and/or other parameters described herein

Optionally, in one embodiment of the invention, the output to the GD_(n)for a respective T_(current) is generated from a weighted sum of e_(n)for the respective T_(current) and the integral of e_(n) for therespective T_(current) (e.g. based on a signal from a PI controller).Optionally, the gas delivery means GD_(n) is controlled using acontroller (VC_(n)) in the form of a PID controller. Optionally, thegroup of respective time points of interest defined with respect to therespective T_(current) define a cumulative time period (T_(variable))beginning at a resetable T_(start) and ending at an incrementallyadvancing time point (T_(end)) equated to the respective T_(current) andthe signal to the GD_(n) applicable to a respective T_(current) iscomputed using only an actual CVG_(n) and/or CVCO₂, and CVG0 and/orCVG_(R) delivered in the time period T_(variable). In another embodimentof the method, the group of respective time points of interest definedwith respect to the respective T_(current) define a cumulative timeperiod (T_(variable)) beginning at a resetable T_(start) and ending at aan incrementally advancing time point (T_(end)) equated to therespective T_(current) and the signal to the GD_(n) for a T_(variable)corresponding to a respective T_(current) is computed based on:

(a) the output of the controller; and

(b) an incremental volume of G₀ presumed to be delivered in the timeinterval ΔT between the respective T_(current) and a ensuing time pointT_(current+) (G₀ ^(P)). Accordingly, based on a predicted concentrationof CO₂ in G₀ ^(P) (FCO₂₀ ^(P)) the signal to the GD_(n) may also deliveran incremental volume of G_(n) that must be added to G₀ ^(P) (G_(n)^(P)) so that the incremental volume of CO₂ in the combined volume of G₀^(P) and G_(n) ^(P) equals FCO₂ ^(T).

A variety of different strategies could be used to add a predictiveelement to the aforementioned approach of keeping the delivered G_(n) instep with the amounts of G₀ delivered so that the e_(n) is lessened orless variable. According to one embodiment herein, the signal deliveredto the GD_(n) is computed based on the sum of the output of thecontroller VC_(n) and a volume of G_(n) that must be added to G₀ ^(P)(G_(n) ^(P)) so that the incremental volume of CO₂ in the combinedvolume of G₀ ^(P) and G_(n) ^(P) equals FCO₂ ^(T). A variety ofalternative methods could be used to compute G₀ ^(P) and FCO₂₀ ^(P).Optionally, G₀ ^(P) for the time interval ΔT corresponding to arespective T_(current) is equated with a pre-defined value, anincremental volume of G₀ delivered during a previous time interval ofinterest, or with an average or weighted average of the volumes of G₀delivered in a plurality of previous time intervals of interest.Optionally, FCO₂₀ ^(P) can be equated with a pre-defined value, aconcentration of CO₂ in the G₀ at a previous time point of interest, orwith an average or weighted average of the concentration of CO₂ in theG₀ at a plurality of previous time points of interest. In general, G₀^(P) and FCO₂₀ ^(P) can be computed based on any combination of pastdata including, but not limited to, incremental volumes of G₀ deliveredor the concentration of CO₂ in G₀, and/or the rate of change of G₀delivery or the rate of change of the concentration of CO₂ in G₀, at oneor a plurality of time points or time intervals of interest. Methods forcomputing G₀ ^(P) and FCO₂₀ ^(P) based on past data include, but are notlimited to, averages, weighted averages, artificial intelligence,pattern recognition, rule definitions, look-up-tables, empiricalformulas, or heuristics.

Optionally, the T_(variable) corresponding to a respective T_(current)is selectable based on a volumetric dimension of CVG₀ or CVG_(R) ofinterest, or a volumetric dimension of CVCO₂ or CVG_(n) of interest, aset of time points defined by an external event or a set of time pointscorresponding to a part of an inspiratory cycle, a full inspiratorycycle or a series of, parts of or full, inspiratory cycles. For example,the device of the present invention may be used to simulate sequentialdelivery of a pre-defined volume of G₀ delivered in the first part ofany inspiratory cycle and a gas having a CO₂ content approximating thesubject's arterial PCO₂ for the remainder of any inspiratory cycle.

As described above, in one embodiment, the GD_(n) is a proportional flowcontrol valve. The invention also encompasses intermittently turning onand off a two way solenoid, etc.

Optionally, the cumulative volume of G_(n) (CVG_(n)) actually deliveredat respective points T₁ . . . T_(current) is obtained via a “volumesensor” (VS_(n)) which can be constituted by any hardware for directlyor indirectly measure a volume of G_(n) e.g. an incremental volume ofG_(n), for example, a spirometer, a flow meter (by computing theintegral of the flow), a CO2 analyzer which can be used, for example, todeduce the flow of G_(n) which is then integrated to arrive at a volumeetc. Input of a cumulative volume of G₀ (CVG₀) or G_(R) (CVG_(R))actually delivered over all time points T₁ . . . T_(current) may can beimplemented by employing the output a second volume sensing means (a VS₀or VS_(R)) depending on whether the volume of G₀ (VS₀) or the totalvolume of respiratory gas (VS_(R)) is being measured and/or computed.

The term “ascertained” when referring to a concentration of CO₂ in G_(n)or G₀ applicable to any respective T_(current) (or in an analogouscontext) is used to broadly refer to a variety of instances e.g. where avalue is determined for a respective T_(current) by a gas analyzer;where the need for ascertaining the CO₂ concentration is obviated by thealgorithm (e.g. the fractional concentration of CO₂ is not directlytaken into account as an input, for example, where the device isparticularly to adapted to a G_(n) consisting entirely of CO₂ or G₀ with0% CO₂); where the concentration of CO₂ in the added gas is a fixedvalue based on a known concentration of CO₂ in the CO₂ containing sourcegas G_(n) (e.g. an inputable preset concentration such as 90% or 100%CO₂) or where the concentration of CO₂ in the G₀ is a fixed value basedon a known concentration of CO₂ in the G₀ (e.g.0% CO₂ in air).

Optionally, the function of the controller VC_(n) is carried out by amicrocontroller which optionally also receives and/or computes thevarious inputs described above including one or more of the following:for each of a group of respective time points of interest T₁ . . .T_(current:) FCO₂ ^(T), CVG_(n), CVG₀ and/or CVG_(R), an error signal(e_(n)) equal to the volume of G_(n) that must be delivered to thesubject with the G₀ so that the cumulative volume of CO₂ in CVG_(R)equals a desired fraction FCO₂ ^(T); the output(s) of a volume sensingmeans (VS_(n) and/or VS₀ and/or VS_(R)) and optionally, the output of agas analyzer. Optionally, the inputs and computations are carried out bya general purpose microprocessor or CPU.

In one aspect, the invention is directed to a computer program productcomprising a computer readable medium (non-transitory) encoded withprogram code for controlling operation of a device, the program codeincluding program code for obtaining input of or computing, for each ofa group of respective time points of interest T₁ . . . T_(current), eachin turn a respective T_(current), a set of parameters for computing anerror signal (e_(n)) equal to an incremental volume of a CO₂ containingG_(n) that must be delivered in step with a G₀ so that the cumulativevolume of CO₂ in CVG_(R) is maintained at a desired fraction FCO₂ ^(T).In one embodiment, the set of parameter includes a respective CVCO₂ andCVG_(R) for each respective T_(current). In one embodiment, the programcode comprises program code for controlling a gas delivery means(GD_(n)). In one embodiment, the program code generates a suitablesignal corresponding to an actual incremental volume of CO₂ needed totargets FCO₂ ^(T) for each respective T_(current) within the group ofrespective time points of interest T₁ . . . T_(current). Any suitablemethod of control known to those skilled in the art, for example, a formof PI or PID control may be included in the program code.

It is understood that any input, computation, output, etc describedherein can be accomplished by a variety of signal processing meansincluding, but not limited to, a programmable processor, a programmablemicrocontroller, a dedicated integrated circuit, a programmableintegrated circuit, discrete analog or digital circuitry, mechanicalcomponents, optical components, or electrical components. For example,the signal processing steps needed for executing the inputs,computations and outputs can physically embodied in a field programmablegate array or an application specific integrated circuit.

In another one aspect, the present invention is directed to a controlsystem for a respiratory gas delivery system that controls thecoordinated output of a carbon dioxide (CO₂)-containing gas (G_(n)) anda second gas (G₀), in a manner that composes a respiratory gas G_(R),the control system comprising:

-   -   for respective time points in a series of time points of        interest:    -   a) means for obtaining input of a cumulative volume of G₀ (CVG₀)        or G_(R) (CVG_(R)) delivered over a period comprising the series        of time points of interest;    -   b) means for obtaining input of a cumulative volume of G_(n)        (CVG_(n) ) or CO₂ (CVCO₂) delivered over a period comprising the        series of time points of interest;    -   c) means for using the input obtained to compute an incremental        volume of G_(n) that must be delivered so that the cumulative        volume of CO₂ in a volume of the respiratory gas of interest        (CVG_(R) ^(I)) equals a target CO₂ concentration (FCO₂ ^(T));        and optionally    -   d) means for controlling a gas delivery means (GD_(n) ) so that        respective incremental volumes of G_(n) delivered target FCO₂        ^(T).

Optionally, the control system includes means to obtain input of a FCO₂^(T). It is understood that the control system is used to deliver therespective components of the G_(R) in a manner that enables therequisite volumes to be tracked, whether the delivery is to an area ofcommon volume or separate volumes organized to be deliveredcoordinately. Optionally, the control system is embodied in a computeras broadly defined herein.

In one aspect, the present invention is directed to a computer readablememory having recorded thereon computer executable instructions forcarrying out one or more embodiments of the above-identified method. Theinvention is not limited by a particular physical memory format on whichsuch instructions are recorded for access by a computer. Non-volatilememory exists in a number of physical forms including non-erasable anderasable types. Hard drives, DVDs/CDs and various types of flash memorymay be mentioned. The invention, in one broad aspect, is directed to anon-transitory computer readable medium comprising computer executableinstructions for carrying out one or more embodiments of theabove-identified method.

In one embodiment, the invention is directed to IC chip designed toimplement a method according to the invention. In one embodiment, theinvention is directed to a printed circuits board comprising one or morehardware components for the implementing a control system as describedabove, for example an IC chip, adapted to implement a method accordingto the invention.

Optionally, the computer readable memory includes machine readable codeto receive input of or compute for each of a group of respective timepoints of interest T₁ . . . T_(current), each in turn a respectiveT_(current):

-   -   (A) a cumulative volume of G_(n) (CVG_(n)) actually delivered at        all time points T₁ . . . T_(current), (optionally an incremental        volume of G_(n) delivered at each respective time point        T_(current) for computing CVG_(n)) or preferably a cumulative        volume of CO₂ (CVCO₂) actually delivered as of all time points        T₁ . . . T_(current), (optionally an incremented volume of CO₂        updated at each respective time point T_(current) within a        series of time points of interest);    -   (B) a cumulative volume of G₀ (CVG₀) or G_(R) (CVG_(R)) actually        delivered at all time points T₁ . . . T_(current) (optionally an        incremented volume of G₀ or G_(R) delivered at each respective        time point T_(current) for computing CVG₀ and/or CVG_(R));    -   (C) in accordance with a concentration of carbon dioxide (CO₂)        in G_(n) and G₀ applicable to the respective T_(current), an        error signal (e_(n)) equal to the volume of G_(n) that must be        delivered in step with the G₀ so that the cumulative volume of        CO₂ in CVG_(R) equals a desired fraction FCO₂ ^(T).

The computer readable memory may also include machine readable code forcontrolling a gas delivery means (GD_(n)) so that the actual incrementalvolume of CO₂ coordinately delivered with CVG₀ (as part of CVG_(R))targets FCO₂ ^(T) (for example, any suitable controller known to thoseskilled in the art, for example, a PI or PID controller).

In another aspect, the present invention is directed to a device (an ICchip), CPU or microcontroller programmed to implement one or moreembodiments of the above method. The program may include machinereadable code as defined above. The program may be recorded on anintegrated or external computer readable memory.

The aforesaid device may optionally include the following: the VC_(n)and optionally, one or more components which serve one or more functionsof: a VS_(n), GD_(n) and optionally a G_(n) gas channeling means forexample a port or G_(n) gas delivery conduit for receiving the G_(n)delivered by the GD_(n).

Accordingly, according to another aspect, the invention is directed to adevice for adding at least one added gas (G_(n)) to an inspiratory gasG₀, to formulate a respiratory gas (G_(R)) for delivery to a subject,and maintaining a targeted concentration of CO₂ in the G_(R),comprising: a processing unit programmed to implement the method definedhereinabove (optionally, a CPU, microprocessor or microcontroller ordedicated circuit) and optionally, the VC_(n) and optionally, theVS_(n), GD_(n) and a G_(n) gas channeling means, for example a G_(n) gasdelivery conduit, for channeling the G_(n) output by the GD_(n).

The G_(n) gas channeling means, optionally in the form of G_(n) deliveryconduit is optionally adapted to be operatively associated with ordirectly fluidically connected to a G₀ or G_(R) gas channeling means,for example a G₀ or G_(R) delivery conduit (e.g. an inspiratory limb ofa breathing circuit) or any other gas channeling means e.g. a dedicatedlimb of a breathing circuit, a patient airway interface, a manifold, forexample, a manifold for receiving multiple added gases or a connectorinterconnecting one or more of the above. Optionally, the device alsoincludes a volume sensor (VS₀) operatively associated with the devicefor determining a cumulative volume of G₀ (or a volume sensor (VS_(R))operatively associated with the device for determining a cumulativevolume of inspired respiratory gas). The device optionally includes a G₀channeling means e.g. a G₀ delivery conduit for delivering aninspiratory gas (G₀) to a subject. The term “delivery” to describe aconduit is used to in the sense of “channel” and does not imply thecapacity to move a gas without a GD_(n). Similarly, the termed“delivered” in the context of outcome of channeling a gas does not implythe capacity to move the gas into the patient's lung, but simplyreleasing a certain volume of gas to be available for spontaneousinhalation or to be moved by a ventilator.

In another aspect, the invention is directed to a respiratory gasdelivery system for delivering a respiratory gas to a subject includinga G₀ delivery system, for example a breathing circuit, a ventilator(manual or mechanical), an anesthetic machine etc.) and a G_(n) deliverysystem incorporating one or more the features of a device or method asdefined herein.

Accordingly in another aspect the invention is directed to a system foradding a carbon dioxide containing gas G_(n) to an inspiratory gas (G₀)stream, to formulate a respiratory gas G_(R), comprising:

(1) A first gas channeling means (optionally a first gas deliveryconduit) for channeling an inspiratory gas (G₀) to a subject;

(2) A volume sensing means (VS₀) operatively associated with the systemfor determining a cumulative volume of G₀ (CVG₀) (or a volume sensingmeans (VS_(R)) operatively associated with the system for determining acumulative volume of inspired respiratory gas (CVG_(R)));

(3) A G_(n) delivery system for maintaining a targeted concentration ofcarbon dioxide (CO₂) in a cumulative inspired volume of the respiratorygas, including:

-   -   (A) a second gas channeling means (optionally a second gas        delivery conduit) operatively associated with the first gas        channeling means for channeling to the subject, coordinately        with the G₀, a controlled volume of G_(n);    -   (B) gas delivery means (GD_(n)) for releasing a variable        incremental volume of G_(n) into the second gas channeling        means;    -   (C) a volume sensing means (VS_(n)) operatively associated with        the device for determining a cumulative volume (CVG_(n)) of        G_(n);    -   (D) at least one computer (for example a dedicated circuit or        CPU programmed to process machine readable instructions) for:        -   a) receiving input of:            -   (A) a target concentration of CO₂ (FCO₂ ^(T)) in any                cumulative volume of inspired respiratory gas;            -   (B) the concentration of CO₂ in G_(n) and G₀ as                applicable;            -   (C) the output of a VS₀ and/or VS_(R);            -   (D) the output of a VS_(n);        -   b) computing for each of a group of respective time points            of interest T₁ . . . T_(current), each in turn a respective            T_(current):            -   (A) a cumulative volume of G_(n) (CVG_(n)) or pure CO₂                actually delivered as of all time points T₁ . . .                T_(current);            -   (B) a cumulative volume of G₀ (CVG₀) or G_(R) (CVG_(R))                actually delivered in as of all time points T₁ . . .                T_(current);            -   (C) with respect to the concentration of CO₂ in G_(n),                an error signal (e_(n)) equal to the volume of G_(n)                that must be delivered to the subject with the G₀ so                that the cumulative volume of CO₂ in CVG_(R) equals a                desired FCO₂ ^(T);        -   c) for each respective T_(current), controlling the gas            delivery means GD_(n) so that the actual incremental volume            of CO₂ delivered to the subject in relation to CVG₀ or            CVG_(R) targets FCO₂ ^(T).

The term computer is used broadly to refer to any device (constituted byone or any suitable combination of components) which may used inconjunction with discrete electronic components to perform the functionscontemplated herein, including computing and obtaining input signals andproviding output signals, and optionally storing data for computation,for example inputs/outputs to and from electronic components andapplication specific device components as contemplated herein. Ascontemplated herein a signal processor, processor or processing device(these terms used broadly and interchangeably unless a narrower meaningis implicit and means a CPU or computer in any suitable form) e.g. inthe form of a computer may use machine readable instructions ordedicated circuits to perform the functions contemplated hereinincluding without limitation by way of digital and/or analog signalprocessing capabilities, for example a CPU, for example a dedicatedmicroprocessor embodied in an IC chip which may be integrated with othercomponents, for example in the form of a microcontroller. Key inputs mayinclude input signals from—a volume sensor such as a flow meter, a gasanalyzer, any type of input device for inputting a CO₂ ^(T) (forexample, a knob, dial, keyboard, keypad, mouse, touch screen etc.) inputfrom a computer readable memory etc. Key outputs include output of acontrol signal to control to a GD_(n), including any control signal froma VC_(n) based on an e_(n) to target CO₂ ^(T), for example PI control orPID control, an output signal to an alarm generating device etc. Avariety of alternative forms of suitable control signals for controllingGD_(n) are well known to those skilled in the art.

In one aspect, a G_(n) delivery system according to the invention ispart of a larger respiratory gas delivery system including a G₀channeling means (for example a port or conduit for conducting the G₀,for example, forming part a manifold and/or one or more parts of abreathing circuit e.g. an inspiratory limb of a breathing circuit) and avolume sensor for obtaining input to determine a cumulative amount or G₀or G_(R) delivered. Optionally, a G_(n) delivery system is an adjunctdevice which includes G_(n) delivery components but does not include oneor both of the first gas channeling means (e.g. a conduit or dedicatedport) for delivering an inspiratory gas (G₀) to a subject or a volumesensor. The invention contemplates that a device according to theinvention may nevertheless receive output from a volume sensor (VS₀)which is operatively associated with the device for determining acumulative volume of inspired G₀ (or an equivalent volume sensor(VS_(R)) operatively associated with the device for determining acumulative volume of delivered respiratory gas). The G_(n) channelingmeans e.g. a port in a manifold or a delivery conduit (alternativelycalled an “added gas delivery conduit”) may be readily adapted to beoperatively associated with (e.g. connected to—the first gas deliveryconduit or an airway interface (e.g. a mask, endotracheal tube etc. thatinterfaces with the subject's airway) in a manner suitable forchanneling G_(n) to the subject in tandem with the G₀. The devicecomputer may be programmed to receive inputs of the VS₀ or VS_(R)optionally in the form of a computed cumulative volume for use accordingto the invention or directly in the form of incremental volumes fromwhich the device computer computes the requisite cumulative volumes.

The term “operatively associated” is generally (unless the contextdictates otherwise) used expansively to mean “functionally associated”,whether directly or indirectly, for a specified or implicit purpose. Forexample, a sensor will be operatively associated with the first gas (G₀)delivery conduit if it directly measures the volume of gas movingthrough the conduit at a selected time point or indirectly measures thevolume of gas by measuring the combined volume of the G_(n) and G₀moving into a subject airway interface and subtracting the volume ofG_(n).

In one embodiment of the devices described above, the output from avolume controller VC_(n) is a based on PID control algorithm, forexample an error signal for a respective T_(current) is generated baseda weighted sum of e_(n) for the respective T_(current), the derivativeof e_(n) for the respective T_(current) and the integral of e_(n) forthe respective T_(current).

Depending on the application, the cumulative inspired volume ofrespiratory gas may be constituted by the volume of a part of aninspiratory cycle, a full inspiratory cycle or a series of, parts of orfull, inspiratory cycles.

In one embodiment of a device according to the invention the second gaschanneling means (e.g. a second gas delivery conduit or added gasdelivery conduit) may be fluidly connected to the gas channeling means(optionally a first gas delivery conduit) to deliver G_(n) into thefirst gas channeling means e.g. delivery conduit. Alternatively, thefirst gas channeling means and the second gas channeling means areindependently connected to a subject airway interface for coordinatelydelivering G₀ and G_(n) respectively into the subject airway interface.

It will be appreciated that each of the key method steps for carryingout the invention can be functionally apportioned to different physicalcomponents or different computer program products or combinations ofboth. Furthermore a device according to the invention may comprise oneor more physical components in the form of sensors (e.g. flow), gasdelivery devices, gas analyzers, gas channeling means, standardelectronic components making up a PCB, input devices for settingparameters etc. The various means for carrying out these steps includewithout limitation one in the same physical means, or different physicalmeans on different devices, the same device or the same devicecomponent. Depending on the number of added gases these components maymultiplied or where possible shared. A device which is directed toimplementing a method of preparing a carbon dioxide (CO₂)-containing gas(G_(n)) that is organized for delivery in tandem with a second gas (G₀),in manner that composes a respiratory gas (G_(R)) and maintains a targetCO₂ concentration (FCO₂ ^(T)) in a cumulative volume of the G_(R) ofinterest (CVG_(R) ^(I)), may comprise:

for each successive time point of interest in a growing time periodcomprising all time points of current interest T₁ to T_(last), eachsuccessive time point in turn a T_(last):

(a) means for obtaining input comprising or sufficient to compute:

-   -   (i) a cumulative volume of G_(R) (CVG_(R)) organized for        delivery as of T_(last) over all time points of current interest        T₁ to T_(last); and    -   (ii) a cumulative volume of CO₂ (CVCO₂) organized to compose        part of the CVG_(R) as of T_(last) in all time points of current        interest T₁ to T_(last); and optionally

(b) means for using the input obtained to compute a respectiveincremental volume of G_(n) that must be delivered as of T_(last) sothat the cumulative volume of CO₂ in the CVG_(R) equals FCO₂ ^(T); andoptionally

(c) means for controlling a gas delivery means (GD_(n)) so that therespective incremental volume of G_(n) targets FCO₂ ^(T).

In at least one general aspect, the invention is directed to a methodfor adding at least one added gas (G_(n)) to an inspiratory gas G₀, toformulate a respiratory gas (G_(R)) for delivery to a subject, and tomaintain a targeted concentration of at least one component of an addedgas G_(n) (DA_(n)) in a volume of the G_(R) (DA_(n) ^(T)), comprisingthe steps of:

(a) obtaining input of confirmed incremental volumes of G₀ and/or G_(R)made available for inspiration by a subject with respect to respectivetime points of interest;

(b) obtaining input of confirmed incremental volumes of G_(n) and/orpure DA_(n) made available for inspiration by a subject with respect tothe respective time points of interest;

(c) at least if required to compute an error signal (e_(n)), obtaininginput of the concentration of DA_(n) in G₀ and/or G_(R) and/or G_(n)with respect to the respective time points of interest (required whereG_(n) is not pure DA_(n) or G₀ contains DA_(n));

wherein the input obtained is cumulatively sufficient to compute, forsuccessive respective time intervals between contiguous points ofinterest, an e_(n) that represents an incremental volume of G_(n) thatmust be delivered to the subject with respect to the respective timeinterval (e.g. for a series of successive time points, each in turn aT_(current), the e_(n) for the incremental interval ending at arespective last T_(current)) so that the cumulative volume of DA_(n)equals DA_(n) ^(T);

d) computing e_(n) for each respective time interval between contiguoustime points of interest;

e) providing an output signal to a gas delivery device (GD_(n)) for eachrespective time interval based on the e_(n) computed for the respectivetime interval such that the cumulative volume of DA_(n) is controlled totarget DA_(n) ^(T).

Each of the individual embodiments of the invention described herein maybe adapted to implement the method described immediately above.

In at least one general aspect, the invention is directed to anapparatus for adding at least one added gas (G_(n)) to an inspiratorygas G₀, to formulate a respiratory gas (G_(R)) for delivery to asubject, and to maintain a targeted concentration of at least onecomponent of an added gas G_(n) (DA_(n)) in a volume of the G_(R)(DA_(n) ^(T)), comprising:

-   -   A) means to:        -   (a) obtain input of confirmed incremental volumes of G₀ or            G_(R) flowed to a subject for time points of interest;        -   (b) obtain input of confirmed incremental volumes of G_(n)            or pure DA_(n) flowed to the subject for the time points of            interest;    -   B) a processor for computing for successive respective time        intervals between contiguous time points of interest, an error        signal (e_(n)) representing the volume of G_(n) to be made        available for inspiration with respect to the respective time        interval so that the cumulative volume of DA_(n) equals DA_(n)        ^(T);    -   C) means for providing an output signal to a gas delivery device        (GD_(n)) for the respective time interval based on the e_(n)        computed for the respective time interval such that the actual        cumulative volume of DA_(n) is controlled to target DA_(n) ^(T).        Input of the incremental volumes of G₀ or G_(R) and G_(n) flowed        to a subject with respect to respective time points of interest        is preferably obtained (e.g. computed) as incremented respective        cumulative volumes corresponding to incremented cumulative time        intervals comprising the time points of interest, each        successive interval cumulating a last new T_(current) or        T_(last).

Each of the individual embodiments of the invention described herein maybe adapted to assemble or implement the apparatus defined immediatelyabove.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 a is a schematic representation of one embodiment of a CO₂delivery device in accordance with the invention illustrating, by way ofexample, optional components and configurations of such a device.

FIG. 1 b is a schematic representation of one embodiment of a CO₂delivery device in accordance with the invention illustrating, by way ofexample, optional components and configurations of such a device.

FIG. 1 c is a schematic representation of one embodiment of a CO₂delivery device in accordance with the invention illustrating, by way ofexample, optional components and configurations of such a device.

FIG. 2 is a schematic representation of one embodiment of a CO₂ deliverydevice in accordance with the invention illustrating an optional schemefor organizing the flow of several added gases G₁ to G_(n) (directlyinto the G₀ stream) and relevant inputs into and outputs from a computerprogrammed to implement this embodiment of the invention.

FIG. 3 is a schematic representation useful for describing keyvolumetric control considerations underlying the presently disclosedscheme for adding one or more gases (G_(n)) containing a desiredcomponent gas DA_(n) (e.g. CO₂) to an inspiratory gas (G₀) streamaccording to one embodiment of the invention.

FIG. 4 is a flow chart illustrating one embodiment of implementing amethod according to the invention and related computer processing steps.

FIG. 5 is an illustration in a graph form of advantages of an embodimentof the invention for adding CO₂ to an inspiratory gas stream.

The term “inspiratory gas” denoted G₀ refers to any gas to which a gasconsisting of or comprising a gas of interest (a component gas) isadded. The G₀ may be a principal gas provided to a subject forinhalation. For example, a ventilated patient may receive oxygenenriched gas as the G₀. The G₀ may also be one or more gases consistingor comprising desired component gases which may be individually orcollectively considered a G₀ with reference to another component gas.Accordingly the invention is concerned with but not limited toconditioning an inspiratory gas in the sense only of a principal gas andin one embodiment of the invention several added gases may be channeledinto a manifold and each or the combination of several of them may be aninspiratory gas with reference to a particular component gas. Therefore,the invention contemplates that the necessary volumetric information isascertained to track actual volumes of the component gas(es) of interestand the volume of gas e.g. the G₀ or G_(R) into which a component gashas been diluted.

The term “volume sensor” (which may also be referred to as a “volumesensing means”) means any device that can be used to directly orindirectly determine the volume of a gas that has passed through abreathing circuit or particular conduit thereof, typically with respectto a reference location in a breathing circuit. The inventioncontemplates that this can be accomplished by a variety of types ofhardware including a flow meter, a gas concentration sensor (forexample, a certain amount of any first gas of known composition can beinferred to have been delivered past a reference point if mixed with anysecond gas of known composition and volume by ascertaining theconcentration of the first gas in a mixture of the first and secondgases), a pressure transducer (for example, an added gas is sourced froma tank of fixed volume, and a pressure transducer in the tank could beused to determine the volume obtained from the tank).

As shown in FIGS. 1 a, 1 b and 1 c, a system for adding CO ₂ to aninspiratory gas stream is exemplified by delivering controlled amountsof CO₂ into a G₀ channelling means exemplified in the form of aninspiratory limb 200 of a breathing circuit. A CO₂ supply means,exemplified by tank 202 of pressurized CO₂, is illustrated. The CO₂ iscarried by a conduit 204 made of inert tubing (does not react with CO₂and preferably other optional components of the gas G_(n) in the tank).Gas leaving the tank of pressurized CO₂ is controlled by one or moreflow regulators (206) for reducing the pressure of the gas coming out ofthe tank 202. For example, the pressure may be first be reduced by asingle pressure regulator 206, or may be initially reduced to a rangeacceptable for a miniature pressure regulator, which in turn reduces thepressure of gas Gn further (e.g. CO₂) to that required at the inlet of agas delivery means 210, for example a means for delivering variableincremental volumes of CO₂ e.g. a valve that opens proportionally to acontrol signal (referred to herein as a proportional flow control valveor proportional control valve). Alternatively, a two way solenoid 236(illustrated in FIG. 1 for a different function) can be turned on an offintermittently to accomplish a form of gas delivery volume control. Apump or blower may serve the purpose in some instances. A computer,optionally in the form of microcontroller 212, optionally incorporates acontroller (e.g. a PID controller) for controlling the output signal tothe proportional control valve 210. The microcontroller 212 receivesinput and provides output via signal carrying means shown (with brokenlines) as signal lines. Most importantly this input comprises: (1) theoutput of a sensor means or sensor 214 which serves to determining theactual volume (a “volume sensor”) of CO₂ output by the proportional flowcontrol valve 210. This volume sensor is optionally a flow meter 214whose instantaneous or total output is integrated to get the incrementalvolume of inspired CO₂, or the total accumulated volume of inspired CO₂,respectively; (2) the output of a second “volume sensor” exemplified asan inspiratory flow meter 218 (output of the respiratory flow meter isintegrated to get the accumulated volume of inspired inspiratory gas G₀)for determining the actual volume of gas being delivered, for example ata selected junction in the inspiratory limb 200. The inspiratory limb200 leads to a patient connection 220 which is or leads to a mask,endotracheal tube, etc. (not shown) generically referred to forconvenience as a subject airway interface. Measurements made by theinspiratory flow meter made at discrete time points T₁ . . . T_(current)(each in succession, as time passes, a respective T_(current)) enablethe controlled delivery of incremental volumes of CO₂ which aregenerally coordinately delivered with the inspiratory gas (G₀) stream,in proportioned increments i.e. a calculated amount of CO₂ whichachieves the targeted fraction of CO₂ in the blended volume ofrespiratory gas G_(R) (FCO2^(T)) by adjusting the cumulative volume ofdelivered CO₂ to match the integrated flow of the inspiratory flow meter218 so that the total volume of CO₂ gas actually delivered matchesFCO2^(T) with respect to the total volume of the delivered respiratorygas of interest (delivered over an incrementally growing time periodT_(variable)). Optionally, a check valve 222 (e.g. Beswick CKVU)prevents back flow through the CO₂ delivery line. One-way check valves224, 226 (e.g. Hans Rudolph 5610) may be constituted by low resistanceone-way valves that prevent the patient from expiring back in to theinspiratory limb 200, and from inhaling via expiratory limb 234. Theseone way valves (224, 226) also protect the respiratory flow meter 218and minimize circuit dead space.

As shown in FIGS. 1 a, 1 b and 1 c, for safety purposes a CO₂ analyzermay be used to continuously monitor the inspired and expired fractionalconcentration of CO₂. As described herein, a gas analyzer may also beindirectly used to a volume of gas passing by its location to the extentthat a more diluted or concentrated gas may be used to determine whatvolumes of gas were mixed.

In one embodiment illustrated, for example in FIG. 1 a, themicrocontroller 212 reads a target % of CO₂ (FCO₂ ^(T)) and all thesignals from the sensors and sends suitable control signals to the valve210 and thereby implements suitable valve control (e.g. PID control). Amonitor 230 displays information to the operator and a visible oraudible signal generator 232 (e.g. a buzzer) may be used for safety tonotify an operator if something goes wrong. In terms of safety featuresthe microcontroller 212 may continuously receive input from the CO₂analyzer 228. If inspired and/or expired CO₂ is high for a definedperiod of time then an optional two-way solenoid valve 236 may beclosed, the proportional flow control valve 210 may be closed, and thebuzzer 232 excited.

FIGS. 1 a, 1 b and 1 c illustrate different configurations related tothe placement of flow sensor 218. In a standard configuration, shown inFIG. 1 a, when the inspiratory limb is connected to a ventilator (notshown) flow sensor may not accurately reflect the tidal volume of gasactually entering the patients lungs because the flow sensor 218measures a compressible volume of gas that is compressed in and expandsthe tubing more proximal to the subject. Gas flowing through the flowsensor 218 may flow around the Y connection through to the expiratorylimb 234. On the other hand, as illustrated in FIG. 1 b, the placementof a flow sensor 218 at the mouth (proximal to the patient connection220) adds dead space which may impair carbon dioxide elimination,especially in children and small adults. Furthermore, it adds bulk andweight to the patient airway interface. As illustrated in FIG. 1 c, across-bridge 208, connecting the inspiratory 200 and expiratory 234limbs, causes the flow sensor 218 to see only gas destined forinspiration by the patient as the compressible volume flows through thecross-bridge preventing passage through the flow sensor 218 or in asense by-passing the flow sensor 218. Optionally, the G₀ gas channelingmeans includes a flow-sensor by-pass means, such as described above, forobtaining an accurate measurement of G₀ tidal volume actually flowing tothe patient. This form of cross-bridge or by-pass means betweeninspiratory and expiratory sides can also be present in the ventilatorsuch that a flow meter downstream thereof (towards the patient) in thetubing leading out to the connection to the inspiratory limb of abreathing circuit measures accurate tidal volumes flowing to thepatient.

As shown in FIG. 2, according to one embodiment of an apparatusaccording to the invention several added gases G₁ to G_(n) sourced fromgas sources 410, 420 and 430, respectively, may optionally be directlyadded into the G₀ stream. A volume sensor (VS₀) 370 is operativelyassociated with the G₀ delivery conduit 55 and is optionally located inthe G₀ conduit 55, optionally along with respective gas analyzersGS_(1,0) to GS_(n,0) (340, 350, 360) for each of the respective addedgases which gases may be present in the inspiratory gas G₀. Relevantinputs into and outputs from a computer 300 programmed to implement thisembodiment of the invention include: inputs from optional gas analyzersGS_(1,0) to GS_(n,0) (340, 350, 360) and GS₁ to GS_(n) (380, 390, 400)(needed where the fractional concentration of gas of interest in anadded gas is unknown or optionally for enhanced safety) and inputs fromvolume sensors 310, 320, 330, (as broadly defined herein) optionallylocated in the respective added gas delivery conduits 315, 325 and 335.Inputs of fractional concentrations of the respective component gasesF_(DA1,R)-F_(DAn,R) enable a controller 345, optionally integrated aspart of the computer 300, to direct outputs to respective gas deliverymeans GD₁ to GD_(n) (355, 365, 375) based on the actual incrementalvolumes of gas delivered by the gas delivery means as determined via therespective volume sensors VS₀ (370) and VS₁ to VS_(n) (310, 320, 330).It will be appreciated that a component gas of interest does not need tobe CO₂ and may be any gas such O₂, Xe, He, H₂, NO, N₂O, H₂S, CO, SF6, ananesthetic, etc. In, for example, a compressed gas form, one or moresuch gases can be added to the G₀ gas to compose a respiratory gasG_(R). The term DA_(n) is generically used herein to refer to acomponent gas of interest and any reference herein to carbon dioxide,except where the context necessarily implies that carbon dioxide isbeing referred to specifically, may be replaced by a reference to DA_(n)or any other specific component gas.

A device according to the invention may therefore comprise a wider ornarrower variety of components that may be particularly useful or morereadily substitutable for implementing a particular application of theinvention. Furthermore, depending on a suitable range of deliverablevolumes of gas in question, optionally attuned to a particular sizerange of a breath (e.g. for a premature human infant or small animal)the sizes and ranges of accuracy of components may be differentlyselected according to well understood design criteria.

In terms of optional embodiments, the GD_(n) is optionally aproportional solenoid valve metering the release of G_(n) from apressurized gas source. The invention also encompasses intermittentlyturning on and off a two-way solenoid valve metering the release ofG_(n) from a pressurized gas source. Optionally, the GD_(n) can be a gaspump, blower, or injector connected to a pressurized or unpressurizedreservoir of G_(n).

Input of CVG_(n) actually delivered during T₁ . . . T_(now) is obtainedvia a volume sensor (VS_(n)) operatively associated with a G_(n)delivery conduit. Input of CVG₀ actually delivered during T₁ . . .T_(now) may be obtained via a second volume sensor (VS₀) operativelyassociated with a G₀ delivery conduit. A volume sensor can beconstituted by any hardware for directly or indirectly measuring avolume of gas, for example, a spirometer, or a flow transducer or gasanalyzer from which the flows of gases can be deduced (and thencomputing the integral of the flow).

The inputs, computations, and outputs described in the aforementionedmethod can be carried out by a variety of signal processing meansincluding, but not limited to, a programmable processor, programmablemicrocontroller, dedicated integrated circuit, programmable integratedcircuit, discrete analog or digital circuitry, mechanical components,optical components, or electrical components.

The VC_(n) can be implemented by a variety of signal processing meansincluding, but not limited to, a programmable processor, programmablemicrocontroller, dedicated integrated circuit, programmable integratedcircuit, discrete analog or digital circuitry, mechanical components,optical components, or electrical components.

A G_(n) gas channeling means, optionally in the form of a G_(n) deliveryconduit, is optionally adapted to be operatively associated with ordirectly fluidically connected to a G₀ channeling means, for example, aG₀ delivery conduit such as the inspiratory limb of a breathing circuit,a patient airway interface, a manifold for receiving multiple gasconnections, or a connector interconnecting one or more of the above.

In one embodiment of the invention, all inputs, computations, andoutputs are performed on a general purpose microcontroller. The G_(n) isa pressurized gas containing a known, fixed concentration of DA_(n). Arapid DA_(n) analyzer is operatively associated with the G₀ deliveryconduit to ascertain the concentration of DA_(n) in G₀. A VS_(n) isimplemented by integrating the output of a flow transducer operativelyassociated with the G_(n) delivery conduit. A VS₀ is implemented byintegrating the output of a flow transducer operatively associated withthe G₀ delivery conduit. The VC_(n) may be a PID controller implementedon a general purpose microcontroller. For each T_(current), GD_(n)receives a weighted sum of the output of VC_(n) and G_(n) ^(P). Theincremental G₀ ^(P) predicted to be delivered in the time interval ΔTbetween the respective T_(current) and a ensuing time point T_(current+)is equated with the incremental volume of G₀ delivered in the timeinterval ΔT ending at T_(current). The GD_(n) is implemented with aseries of pressure regulators and a proportional solenoid valve meteringthe release of G_(n) from the pressurized source. The G_(n) deliveryconduit is directly fluidically connected to the G₀ channeling means sothat the G_(n) is directly delivered into the G₀ stream.

As shown in FIG. 3, implementation of the invention, preferably takesinto account a cumulative volume of all of the several components of arespiratory gas G_(R) delivered to a subject including the respectivevolumes of one or more added gases V₁, V₂ . . . V_(n) which arecoordinately delivered with an inspiratory gas (G₀) stream, inproportioned increments i.e. a calculated amount of G_(n) which achievesthe targeted fraction of DA_(n) in a volume of G_(R) (DA_(n) ^(T)) isconsistently added to keep step with one or more recent incrementalamounts of G₀ and other added gases flowed to the subject. The term“coordinately” means involving coordination so as to update the fractionof DA_(n) in a volume G_(R) to a desirable extent in terms of frequencyand accuracy. Optionally, keeping step with new incremental volumetricamounts of delivered G₀ takes full advantage of the capabilities of thehardware of choice. For example, typical cost-effective hardware may becapable of delivering a proportioned amount of G_(n) (relative to anupdated cumulative volume of G₀ including the last confirmed incrementalvolume of G₀ flowed to the subject) containing a known/determinedfraction DA_(n) to match DA_(n) ^(T)—every millisecond. The curved arrowis used to imply controlled and confirmed (via some form of sensor)volumetric addition (e.g. via an appropriately controlled gas meteringdevice e.g. a proportional solenoid under PID control) of a discretecorrective volume of a gas G_(n) containing a component gas of interest(DA_(n)) to a confirmed total volume of delivered gas (including V₁ . .. V_(n), V₀ and optionally DA_(n))—the confirmed cumulative G_(R) volume(confirmed via cooperative action of a plurality of sensors of a broadlyvarying type and location of placement). It is understood that G_(n) maybe made up entirely (100%) of DA_(n). As described herein, incrementalamounts of DA_(n) flowed to the subject are preferably at least“retrospectively corrective” to target DA_(n) ^(T), and as describedbelow may optionally a “predictively corrective” component (inasmuch asa predictive strategy can be termed “corrective” when serving theoptional purpose of facilitating a retrospectively corrective strategy).

V_(DAn) (represented by the oval area 40) is an accumulated volume ofthe component gas of interest that forms part of the volume of G_(R)delivered in virtue of being added at full concentration (G_(n) is 100%DA_(n)) or blended (as illustrated) into one or more of V₁, V₂ . . .V_(n). DA_(n) may optionally also be a component of inspiratory gas G₀.An error signal e_(n) according to a simple embodiment of the inventionis the volume of gas G_(n) that is needed to be delivered (based on whaton has been “definitively” already delivered) to carry with it enough ofthe component gas of interest to ensure that the resulting amount ofthis component gas in a volume of the respiratory gas G_(R) isincrementally maintained (subject to hardware time lags) and thereforeconsistently (to the extent practicable or desired) in the sameproportion vis-à-vis the total volume of “definitively” delivered G_(R)regardless of the changing total volume of gas that has been deliveredto the subject. “Definitively” delivered amounts of G_(n) and G_(R) arenot amounts that the hardware would have delivered if respondingperfectly to flow settings but volumes that requisite “sensors”determine have indeed flowed through the pertinent gas deliveryconduits. The term “definitively” is used superfluously in the presentdescription of FIG. 3 for extra emphasis to distinguish amountstheoretically flowed to the subject (the term “delivered” when used torefer to a volume of a gas implies a volume measured by some form ofdevice—generically called a “volume sensor”—that directly or indirectlymeasures or enables volume computation “delivered” is considered tosufficiently distinguish a “flow setting” or other “unverified delivery”modality used in prior devices). Variations on the above-described basicapproach of “incrementally” correcting to a desired relativeproportion—delivered DA_(n) in delivered G_(R) (retrospective) includeadjunct “predictive correction” strategies for optimizing the errorsignal. Sub-optimal correction on the other hand may vary the size rangeof volumetric increments of G₀ being corrected—the invention is bestexploited by correcting small increments of newly delivered gas,optionally, but not necessarily, the smallest increments possible havingregard to inherent limitations the hardware available or selected (e.g.cost effective) for use. In one embodiment, adjunct predictivecorrection involves predicting how much the volume of G_(R) will growfrom delivery of G₀ in one or more ensuing increments of time (typicallyby predicting one or more ensuing incremental volumes of G₀ based one ormore recent G₀ sensor readings) and computing an accommodative errorsignal even before the new gas is definitively delivered into thecumulative volume of G_(R). According to another embodiment, thecomputed e_(n) may take into account, only amounts of G₀ and G_(n)definitively delivered. Variations on “computing” the error signal,involving a predictive correction factor are understood as adjunctstrategies that are not inconsistent with baseline retrospectivevolumetric correction that broadly defines the invention in one aspect.Aside from “computing” a baseline error signal retrospectively, acontroller, for example a PI or PID controller, would conventionally beused to appropriately implement the corrective e_(n). Accordingly,compensating for hardware limitations inherent in delivering e_(n) maybe seen to represent a distinct aspect of the totality of the volumetriccorrective measure that would be expected to be implemented by anengineer in implementing the invention.

It may be appreciated that the strategy of the invention may beimplemented to a useful extent if the incremental gas proportioning isconsistent in the first part of inspiratory cycle (see FIG. 5) even ifdone in less than optimally small sequential as opposed to sporadicand/or wider spaced time increments. The first part of the inspiratorycycle of interest is the volume that destined to enter the alveoli asopposed to dead space volumes. Furthermore, in theory, the desired orchosen fraction of DA_(n) in G_(R) may be so small that computationalinclusion of DA_(n) as a necessary part of G_(R) could be obviated forsmall cumulative volumes of DA_(n). Accordingly, the formulas andstrategic approaches presented herein address embodiments of and optionswith respect to best and/or most universal practices and don't purportto cover all sub-optimal or circumventive strategies of exploiting theinvention.

As shown in FIG. 4, one embodiment of a method (and related algorithm)according to the invention, may be expressed as a series of stepscarried out with respect to each time increment T_(current) (optionallya time increment that is optimized having regard to time delays of thecomputer, controllers, gas delivery means and sensors (volume, gasanalyzer), wherein the computer:

-   -   1. Reads inputs as exemplified in FIG. 4 (70)    -   2. Calculates (90) the accumulated inspired volume of G₀ (CVG₀)        by adding the volume of G₀ inspired at the respective        T_(current) (to the accumulated volume of G₀ determined as at        the previous respective T_(current) (CVG₀₋)) as measured by VS₀    -   3. Calculates (90) the accumulated inspired volume of each G_(n)        (CVG_(n)) by adding the volume of G_(n) inspired for the        respective T_(current) (to the accumulated volume of G_(n)        determined as at the previous respective T_(current) (CVG_(n-)))        as measured by VS_(n)    -   4. For each DA_(n), determines (either from measurement or        otherwise) F_(DAn,0) (80)    -   5. For each DA_(n), determines (either from measurement or        otherwise) F_(DAn,n) (80)    -   6. For each DA_(n), calculates (100) the accumulated inspired        volume of pure DA_(n) (CVG_(DAn)) by adding the volume of G₀        inspired the respective T_(current) as measured by VS₀        multiplied by F_(DAn,0) at T_(current), and adding the volume of        G_(n) inspired during the time interval ending in T_(current) as        measured by VS_(n) multiplied by F_(DAn) during the respective        T_(current) (it will be appreciated that this type of        computation may accomplished by calculating (90) the accumulated        inspired volume of each G_(n) (CVG_(n)) by adding the volume of        G_(n) inspired during the respective T_(current) especially        where fractional concentration of DA_(n), in G_(n) is constant        or is consistently 100%).    -   7. For each DA_(n), calculates (110) an error signal (e_(n))        equal to the volume of G_(n) that must be added to the        accumulated inspired volume of respiratory gas (CVG_(R)) so that        the volume of inspired DA_(n) composes the target concentration        of DA_(n) (DA_(n) ^(T) or F_(DAn,R)) in CVG_(R) (optionally the        projected total inspired volume of respiratory gas at        T_(current+))

$\frac{{CVG}_{DAn} + {F_{DAn} \cdot e_{n}}}{{CVG}_{0} + {CVG}_{n} + e_{n}} = F_{{DAn},R}$$e_{n} = \frac{{F_{{DAn},R}\left( {{CVG}_{0} + {CVG}_{n}} \right)} - {CVG}_{DAn}}{F_{DAn} - F_{{DAn},R}}$

-   -   8. Delivers a signal to each GD_(n) generated from the weighted        sum of the current value of e_(n), the derivative of e_(n), and        the integral of e_(n) (not shown).

The term DA_(n) (and, as applicable, terms which reference DA_(n) suchas F_(DAn) and CVG_(DAn)) may for convenience be understood to be usedexpansively to reference embodiments of the invention in which there isone DA_(n) as well as multiple DA_(n)s (more precisely DA_(1-n)) sinceDA_(n) in the latter scenario can be understood, if interpreted in arestrictive sense, to mean the last in the series 1 to n. In context,where more than one “DA_(n)” is delivered as part of the cumulativevolume of respiratory gas G_(R), with respect to each “DA_(n)” (strictlyspeaking each respective DA₁ . . . DA_(n)), each other “DA_(n)” can beunderstood to be taken into account as part of the G₀ and hence theaforementioned generic formula for the error term e_(n) should beunderstood broadly to be generically applicable to each respective“DA_(n)” (DA_(1 . . . n)) based on the assumption that the volumes ofthe added gases other than the one for which the computation is beingmade are taken into account as part of the G₀. The (+) sign withreference to a time point is used herein to refer to a future time point(not yet a T_(current)) for which actual delivered (output by a G_(n)specific gas delivery device or ventilator) volumes of a component gasand G₀/G_(R) have not been ascertained. A minus (−) sign may be used torefer to a time point before a respective T_(current) e.g. the mostrecent T_(current) for which actual delivered (output) volumes have beenascertained.

It will be appreciated from the foregoing description that e_(n) may bea corrective volume to bring the concentration of DA_(n) in line withDA_(n) ^(T) as at T_(current) without taking into account theincremental volume of G₀ expected to be delivered by the next respectiveT_(current+1). Alternatively, the computation may take into account theexpected incremental volume of G₀ expected to be delivered by the nextrespective T_(current+) and hence the projected total of volume ofrespiratory gas expected to be delivered by the next T_(current)including the e_(n) and its DA_(n) content.

As shown in FIG. 5, panel A, a device according to the inventionimplements a form of closed loop volume control that enables the flow ofG₁ to maintain a target concentration of G1 in the total inspiredvolume, as early as possible in the breath. As shown in Panel B, this isespecially important and advantageous with respect to the first part ofa breath that fills the alveoli. As seen in Panel B, belated matching ofthe theoretical flow without later compensation accumulates volumetricerror that will not achieve the targeted concentration of DA_(n) inG_(R) in the volume of G_(R) destined to be part of volume of gasentering the alveoli. FIG. 5 is described in more detail below.

In one aspect, the volume of gas containing DA_(n) is ideally deliveredas part of the expanding volume of gas that is alveolar gas and not deadspace gas. This is explained with reference to FIG. 5 described in moredetail below.

The invention can therefore be understood to be broadly directed to amethod for adding at least one added gas (G_(n)) to an inspiratory gasG₀, to formulate a respiratory gas (G_(R)) for delivery to a subject,and to maintain a targeted concentration of at least one component of anadded gas G₀ (DA_(n)) in a volume of the G_(R) comprising the steps of:for each of a series of time points of interest (generally time pointsin which G₀ is being coordinately delivered with G₀):

-   -   (a) obtaining input of confirmed incremental volumes of G₀ or        G_(R) flowed to a subject;    -   (b) obtaining input of confirmed incremental volumes of G₀ or        pure DA_(n) flowed to a subject;    -   c) computing for any respective T_(current) an error signal        (e_(n)) equal to the volume of G_(n) that must be coordinately        delivered to the subject with the G₀ so that the cumulative        volume of DA_(n) equals DA_(n) ^(T);    -   d) for any respective T_(current) providing an output to GD_(n)        based on the e_(n) computed for the respective T_(current)        whereby the actual cumulative volume of DA_(n) (generally        coordinately delivered with CVG₀ as part of CVG_(R)) is        controlled to target DA_(n) ^(T).

Thus in a broader aspect, the present invention relates to a device,method and system for delivering at least one added gas into aninspiratory gas stream to formulate a blended respiratory gas in amanner that continuously maintains a target concentration of the addedgas in a volume of inspired respiratory gas, for example, over thecourse of a breath or a volumetrically definable part thereof or aseries of partial or full breaths. The inspiratory gas may be aprincipal gas stream delivered to a patient such as air optionallyhaving an enhanced oxygen content or air and oxygen combined with ananesthetic gas delivered by a ventilator or anesthetic machine but mayalso be comprised of several additive gases delivered individually or inblended form according to a method/device according to the invention.

A goal of most respiratory gas blenders is to deliver a targetconcentration of an additive gas into the inspired stream. Previously,this has been done by measuring the inspiratory flow and sending asignal to a flow controller to provide a flow of additive gasproportional to the inspired stream. Such a “flow-based control” systemessentially tries to maintain the instantaneous concentration of theadditive gas in the inspired gas at the target value. However, due topractical limitations of flow transducers and flow controllers, mostnotably finite response times, it is not possible for a flow controllerto exactly “track” the inspired gas stream. Therefore, at any timeduring the breath, the instantaneous concentration of additive gas inthe inspired stream may not be equal to the target concentration.Moreover, the overall concentration of additive gas in the accumulatedinspired volume will not be equal to the target concentration.Furthermore, the design of previous respiratory gas blending systemsoverlooks that it is the concentration of additive gas, by volume, inthe volume of inspired gas that reaches the alveoli that is the mostimportant factor in many physiologic, therapeutic and/or diagnosticcontexts.

The simplest gas blending systems try to match the flow of additive gasto the inspired stream with an open loop signal to a flow controller.That is, the actual flow of additive gas delivered by the flowcontroller is not monitored. If there is a systematic error/offset inthe flow delivered by the flow controller, the flow of additive neverreaches the target flow rate. Therefore, the instantaneous concentrationof additive in the inspired stream never reaches target, and theconcentration by volume in the accumulated inspired gas is always inerror.

More complex blending systems try to match the flow of additive gas intothe inspiratory gas stream with a closed loop signal to a flowcontroller. That is, the actual flow of additive gas delivered by theflow controller is monitored. If there is a systematic error/offset inthe flow delivered by the flow controller, the signal to the flowcontroller is adjusted until the flow of additive reaches the desiredflow rate. Therefore, the concentration of additive in the inspiredstream may reach the target value as the breath proceeds, but because ofan obligatory delay in response of the flow controller for the additivegas, the overall concentration by volume will always be less than thetarget concentration set at the beginning of the breath.

In one aspect, the present invention contemplates a control system inwhich the overall concentration of additive gas, in the volume inspiredgas entering into the alveoli, reaches the desired value.

The invention contemplates that one or more additional gas deliveryconduits may be operatively connected to or otherwise operativelyassociated with (via coordinated delivery into an airway interface) theG₀ delivery conduit for coordinately delivering a controlled volume ofan added gas G_(n) (or controlled volumes of a plurality of added gasesG₁ to G_(n)) with the G₀ stream, wherein each G_(1-n) is at leastpartially composed of a respective desired additive gas (DA_(1-n)). Inone embodiment, each gas delivery conduit carrying an added gas isoperatively associated with a volume controller for controlling thevolume of gas coordinately delivered with the G₀, a volume sensoroperatively associated with the added gas delivery conduit forcontinuously measuring the accumulated volume of the added gas.Optionally, where the fractional concentration of the added gas in G₀ isnot known, a means (for example a gas analyzer), operatively associatedwith the G₀ delivery conduit, may be employed to measure, optionallycontinuously, the fraction of the added gas in the G₀ delivery conduit.Optionally, for example for a given G_(n), where the fractionalconcentration of the desired added gas in G_(n) (F_(DAn)) is not known,a means, operatively associated with the G_(n) delivery conduit, forexample a gas analyzer may be employed to measure, optionallycontinuously, F_(DAn) in the G_(n) delivery conduit (GS_(n)). Forexample, in one embodiment, for a gas G_(n), the device may comprise:

-   -   (1) A volume controller (VC_(n)) for controlling the volume of        G_(n) added to G₀    -   (2) A volume sensor (VS_(n)) operatively associated with the        G_(n) delivery conduit for continuously measuring the        accumulated volume of inspired G_(n)

Optionally, where the fractional concentration of DA_(n) in G₀(F_(DAn,0)) is not known, a means, operatively associated with the G₀delivery conduit, to measure continuously F_(DAn,0) in the G₀ deliveryconduit (GS_(n,0))

-   -   (3) A computer that takes input of:        -   A target concentration of each DA_(n) in the accumulated            inspired volume (F_(DAn,1))        -   The output of VS₀        -   The output of each VS_(n)        -   Each _(FDAn,0) (either known or measured)

Each F_(DAn,0) (either known or measured)

-   -   -   And provides output to each VC_(n).

On inspiration, gas entering the mouth or nose is conducted to the lungthrough a series of conduits consisting nasopharynx, oropharynx, tracheaand bronchi. From the point of view of gas exchange, these areconsidered conducting vessels directing gas to the alveoli. As theseconducting vessels do not contribute substantially to gas exchange, theyare termed anatomical deadspace. In an average adult, they consist ofabout 2 ml per kg of body mass, or about 150 ml for the average adult.The alveoli are small saccules where the gas comes into close contactwith blood and gas exchange takes place.

The distribution of gas during inspiration is well understood. At endexpiration, the lung volume is smallest. In the course of inhalation gasis drawn through the anatomical deadspace into the alveoli. At endinspiration, the inspired gas is distributed between the alveoli and theanatomical deadspace. Note the last inhaled gas is retained in theanatomical deadspace. Physiologically the alveoli acts like a mixingchamber where the accumulated gases are mixed. The physiologic effect ofan inhaled gas is determined by its net concentration once it has mixedin the alveolar space, that is, its fractional volume in the alveoli.Its instantaneous inhaled concentration is only important to the extentthat it affects the net volume of that gas in the inspired volume.Although the flow-based controllers can reach an instantaneous targetconcentration of additive in the inspired stream, they are not directedtowards providing a net concentration of a gas in the alveolar spacewhere gas exchange takes place and where the net concentration of theadded gas exerts its pharmacologic effect. This is illustrated in FIG.5. The model is that of a subject being ventilated by a ventilator thatprovides a square wave inspiratory flow of G₀ (this simplest of cases isused for illustrative purposes; the principle herein described appliesto any inspiratory flow pattern by a ventilator or via spontaneousventilation) and a target concentration of component gas 1 (G₁). Arequired flow of G₁ is required to attain this target concentration ofG₁ in the total inspired gas. At the beginning of inspiration theresponse delay in the flow controller results in a ramp up to targetflow. The effect on the G₁ concentration of the gas in the alveoli—thecumulative volumetric error resulting from the shortfall in theinstantaneous concentration of additive G₁ in the inspired stream duringinhalation—is illustrated in the lower part of the figure. Note that thedifference in the volume of G₁ delivered to the alveoli, as representedby the difference between the between the curves “target flow G₁” andthat of the flow-based controllers, results in the volumetricconcentration of G₁ in the inspired gas reaching the alveoli alwaysbeing less than the desired concentration, The instantaneousconcentration of additive in the inspired stream is in greatest error atthe start of the breath. Therefore, early terminations of the breathincrease the discrepancy between desired concentration and actualconcentration of G₁ in the volume of inspired gas reaching the alveoli.

Previous devices have been designed on the premise that a response delayof a flow-based controller at the start of the breath is mirrored by anovershoot in G₁ flow at the termination of the breath. Over the wholebreath, this may result in an average alveolar G₁ concentration at thedesired level if the acceleration and deceleration profile of the breathare symmetrical. However with respect to ventilation, as illustrated inthe lower part of FIG. 5, only the initial part of the breath reachesthe alveoli. The overshoot in G₁ flow at the termination of the breathin our model of a square wave inspiratory flow occurs during exhalationand provides no compensation to the lung concentration. With moresinusoidal inspiratory gas flow, there may be excess flow of G₁ as theinspiratory flow of G₀ slows down. However, at least part of theterminal aspect of the breath where the compensation takes place withflow-based control always resides in the anatomical deadspace and theincreased compensatory flow of G₁ does not reach the alveoli.

By contrast, a closed loop volume-based control provides earlyreconciliation of the G₁ volume and the inspired volume of G₀ such thatthe net inspired concentration of G₁ is at the desired level very earlyin the breath. In practical terms, a volume controller according to theinvention can provide fully compensated alveolar concentrations of G₁within as little as 10 ml of inspired volume and typically within 20-50ml. Premature terminations of breaths after this level is reached wouldnot affect the physiologically important net inspired concentration ofG₁ in the alveolar compartment of the lung.

Furthermore, with respect to the finite response time of any flowcontroller, the shorter the breath, and the greater the inspiratoryflow, the more significant the delay period of the flow controllerbecomes with respect to providing the overall volumetric concentrationof additive gas. Therefore for rapid breathing, where inspiratory flowsare high and inspiratory times short, errors of DA_(n) volumetricconcentrations in the alveoli are magnified by response delays of flowcontrollers. Furthermore, even flow controllers with very rapid responsetimes may still accumulate physiologically important errors ofconcentrations of DA_(n), particularly where DA_(n) is a potentphysiologic molecule (defined as having a large physiologic effect for asmall change in concentration), in the overall volumetric concentrationof DA_(n) in the accumulated inspired volume.

The system according to the invention operates a closed control loop inorder to maintain the concentration of additive, by volume, in theaccumulated inspired volume at a target value throughout the breath. Ateach point in time, the total inspired volume and the total volume ofinspired additive is assessed. An error signal is generated equal to thevolume of additive that must be added to the inspiratory gas stream sothat the overall concentration of additive, by volume, in the gasaccumulated in the lung during inspiration will be equal to the targetvalue throughout the breath. The error signal is provided to a volumecontroller which provides a signal to a gas delivery means(alternatively called a gas delivery device). This maintains theconcentration of additive, by volume, in the accumulated inspired volumeat the target value throughout the breath.

As described below, the invention contemplates that multiple gases canbe combined according to a method of the invention or using a device,computer program product (including any known format in which therequisite program code can be recorded or hard-wired), processor orsystem according to the invention based on adaptations described hereinand evident to those skilled in the art. A reference to blending ordelivering a G_(n) in tandem with a G₀ that does not explicitly specifya single G_(n) and that can be understood to be a general case in whichthere is more than one added gas having the same or a differentcomponent gas of interest are meant to disclose this general case of theinvention in which permutations and adaptations to accommodate more thanone added component are understood to be related. Furthermore each ofthe general classes and specific embodiments of the invention are meantto refer back to the variety of aspects of the invention describedherein and any logistical permutation of these various classes of andspecific embodiments are understood to be described within the generalconcepts for implementing the invention elaborated above. Therefore,while a number of exemplary aspects and embodiments have been discussedabove, those of skill in the art will recognize certain modifications,permutations, additions and sub-combinations thereof. It is thereforeintended that the foregoing description and following appended claimsand claims hereafter introduced are interpreted to include all suchmodifications, permutations, additions and sub-combinations as arewithin their true spirit and scope. Alternative terms for any features,elements, components etc of the invention as defined herein are notmeant to be differentiated by virtue of the use of alternative languageand each term is intended to be given its broadest meaning consistentwith the context and the function it serves according the description ofthe invention as a whole. The scope of the claims should not be limitedby the preferred embodiments, but should be given the broadestinterpretation consistent with the description of the invention as awhole.

REFERENCE LIST

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1-73. (canceled)
 74. An apparatus for adding a carbon dioxide (DA_(n))containing gas (G_(n)) to an inspiratory gas G₀, to formulate arespiratory gas (G_(R)) for delivery to a subject, comprising: a controlsystem operable to maintain a targeted concentration (DA_(n) ^(T)) ofcarbon dioxide in a volume of the G_(R), the control system beingoperatively associated with: A) input means configured to: (i) obtaininput of confirmed incremental volumes of one of G₀ and G_(R) flowed toa subject with respect to time points of interest; and (ii) obtain inputof confirmed incremental volumes of one of G_(n) and pure DA_(n) flowedto the subject with respect to the time points of interest; B) aprocessor configured for computing, for successive respective timeintervals between contiguous time points of interest, an error signal(e_(n)) representing a volume of G_(n) to be made available forinspiration with respect to the respective time interval so that acumulative volume of DA_(n) equals DA_(n) ^(T); C) a controllerconfigured for providing an output signal to a gas delivery device(GD_(n)) for the respective time interval based on the e_(n) computedfor the respective time interval such that the cumulative volume ofDA_(n) is controlled to DA_(n) ^(T).
 75. An apparatus according to claim74, wherein the input means comprises at least one volume sensor.
 76. Anapparatus according to claim 75, wherein the processor is configured tocompute a cumulative volume of at least one of G₀ and G_(R) with respectto respective cumulative time intervals comprising the time points ofinterest, each a respective T_(current), and cumulative volumes of G_(n)with respect to respective cumulative time intervals comprising the timepoints of interest.
 77. An apparatus according to claim 74, wherein theoutput to the GD_(n) for a respective T_(current) is generated from aweighted sum of e_(n) for the respective T_(current) and the integral ofe_(n) for the respective T_(current).
 78. An apparatus according toclaim 77, wherein the GD_(n) is controlled using controller selectedfrom the group consisting of a PI controller and a PID controller. 79.An apparatus according to claim 78, wherein the processor is configuredto cumulate time points defining respective cumulative time periods(T_(variable)) beginning at a resetable T_(start) and ending at anincrementally advancing time point (T_(end)) equated to a last timepoint of interest T_(current) and wherein the signal delivered to theGD_(n) is computed based on: a) the output of the controller; and b) anincremental volume of G₀ (G₀ ^(P)) expected to be delivered in a timeinterval ΔT between the respective T_(current) and a ensuing time pointT_(current).
 80. An apparatus according to claim 79, wherein an expectedincremental volume of G₀ expected to be delivered in the time intervalΔT corresponding to a respective T_(current) is equated with theincremental volume of G₀ delivered at the respective T_(current).
 81. Anapparatus according to claim 79, wherein an expected incremental volumeof G₀ expected to be delivered in the time interval ΔT corresponding toa respective T_(current) is equated with a weighted average of theincremental volumes of G₀ delivered in a plurality of time points ofinterest within T_(variable).
 82. An apparatus according to claim 79,wherein the T_(variable) corresponding to a respective T_(current) isselectable based on a volumetric dimension of one of CVG₀ and CVG_(R) ofinterest, and a set of time points corresponding to at least part of atleast one inspiratory cycle.
 83. An apparatus according to claim 74,wherein the GD_(n) is a proportional control valve.
 84. An apparatusaccording to claim 78, wherein input of a cumulative volume of G_(n)(CVG_(n)) and a cumulative volume of one of G₀ (CVG₀) and G_(R)(CVG_(R)) is obtained from a set of volume sensors (VS) selected from atleast one of a flow meter and a gas analyzer and from a computer forprocessing output of the volume sensors (VSs).
 85. An apparatusaccording to claim 84, comprising a G_(n) delivery conduit, a gasdelivery means GD_(n) and a volume controller VC_(n).
 86. An apparatusaccording to claim 74, wherein the concentration of DA_(n) in G_(n)applicable to any respective T_(current) is determined by a gasanalyzer.
 87. An apparatus according to claim 74, comprising: A) a G_(n)channeling means for channeling coordinately with the G₀, an added gasG_(n) comprising carbon dioxide; (B) a gas delivery device or means(GD_(n)) operatively associated with the G_(n) channeling means ofvariable incremental amounts of G_(n); (C) a volume sensor (VS)operatively associated with the apparatus and configured for determiningan actual incremental volume of G_(n) being delivered at a respectivetime point T_(current); (D) a computer programmed to: a) receive inputor store input of a target concentration of carbon dioxide (DA_(n) ^(T))in a volume of the G_(R); b) use, receive or store input of data that istranslatable into a concentration of DA_(n) in G_(n) applicable to arespective time point T_(current); c) receive the output of the VS; d)receive data representing an incremental volume of one of G₀ and G_(R)being delivered at a respective time point T_(current); e) for arespective T_(current), compute a cumulative volume of one of G_(n)(CVG_(n)) and DA_(n) (CVG_(DAn)) equated to a sum of the actualincremental amounts of one of G_(n) or DA_(n), coordinately deliveredwith G₀ in a group of respective time points T_(current) of interest; f)compute or receive input of a cumulative volume of one of G₀ (CVG₀) andG_(R) (CVG_(R)) with respect to which DA_(n) ^(T) is sought to bemaintained, the cumulative volume including the sum of all incrementalvolumes of G₀ or G_(R) delivered in the group of respective time pointsT_(current) of interest; g) compute for any respective T_(current) anerror signal (e_(n)) equal to the volume of one of G_(n) and DA_(n) thatmust be coordinately delivered to the subject with the G₀ so that thecumulative volume of DA_(n) equals DA_(n) ^(T); h) for any respectiveT_(current) provide an output to GD_(n) based on the e_(n) computed forthe respective T_(current) whereby the actual cumulative volume ofDA_(n) is controlled to target DA_(n) ^(T).
 88. An apparatus accordingto claim 87, wherein the group of respective time points of interestdefined with respect to the respective T_(current) define a cumulativetime period (T_(variable)) beginning at a resetable T_(start) and endingat a an incrementally advancing time point (T_(end)) equated to therespective T_(current) and wherein the signal to the GD_(n) for arespective T_(current) is computed based on: a) the output of theVC_(n); and b) an incremental volume of G₀ (G₀ ^(P)) expected to bedelivered in the time interval ΔT between the respective T_(current)(T_(end)) and a ensuing time point T_(current) by adding the output ofthe VC_(n) to a volume of G_(n) that must be added to (G_(n) ^(P)) sothat the incremental volume of DA_(n) in the combined volume of G₀ ^(P)and G_(n) ^(P) equals DA_(n) ^(T).
 89. A method for adding at least oneadded carbon dioxide containing gas (G_(n)) to an inspiratory gas G₀, toformulate a respiratory gas (G_(R)) for delivery to a subject,comprising: maintaining a targeted concentration (DA_(n)T) of a carbondioxide constituent (DA_(n)) of an added gas G_(n) in a volume of theG_(R) by: (a) obtaining input of confirmed incremental volumes of atleast one of G₀ and G_(R) made available for inspiration by a subjectwith respect to respective time points of interest; (b) obtaining inputof confirmed incremental volumes of G_(n) made available for inspirationby a subject with respect to the respective time points of interest; (c)as necessary, obtaining input of the concentration of the at least oneof DA_(n) in G₀ and G_(R) and G_(n) with respect to the respective timepoints of interest; wherein the input obtained is cumulativelysufficient to compute, for successive respective time intervals betweencontiguous points of interest, an e_(n) that represents an incrementalvolume of G_(n) that must be delivered to the subject with respect tothe respective time interval between successive time points T_(current),so that the cumulative volume of DA_(n) equals DA_(n) ^(T); d) computinge_(n) for each respective time interval between contiguous time pointsof interest; and e) providing an output signal to a gas delivery device(GD_(n)) for each respective time interval based on the e_(n) computedfor the respective time interval such that the cumulative volume ofDA_(n) is controlled to target DA_(n) ^(T).
 90. A method according toclaim 89, wherein input of confirmed incremental volumes of the at leastone of G₀ and G_(R) are obtained in the form of computed cumulativevolumes of the at least one of G₀ and G_(R) with respect to respectivecumulative time intervals comprising the time points of interest, andwherein input of confirmed incremental volumes of G_(n) is obtained inthe form of computed cumulative volumes of G_(n) with respect torespective cumulative time intervals comprising the time points ofinterest.
 91. A method according to claim 89, wherein the GD_(n) iscontrolled using a controller selected from the group consisting of a PIcontroller and a PID controller.
 92. A method according to claim 90,wherein a processor obtains inputs including confirmed incrementalvolumes of G_(n) and at least one of G₀ and G_(R) sufficient to compute:a) cumulative volumes of G_(n) and the at least one of G₀, and G_(R)with respect to the respective cumulative time intervals comprising thetime points of interest; and b) e_(n) with respect to the respectivecumulative time of intervals based on the cumulative volumes of G_(n)and the at least one of G₀, and G_(R); and wherein the time points ofinterest, each in turn a T_(current), define respective cumulative timeperiods (T_(variable)) beginning at a resettable T_(start) and ending atan incrementally advancing time point (T_(end)) equated to the lastrespective T_(current) and wherein the e_(n) corresponding to arespective T_(current) is computed by the processor using CVG_(n) andthe at least one of CVG₀, and CVG_(R) delivered in the time periodT_(variable).
 93. A method according to claim 90, wherein the signaldelivered to the GD_(n) is computed based on: a) the output of thecontroller; and b) an incremental volume of G₀ (G₀ ^(P)) expected to bedelivered in the time interval ΔT between the respective T_(current) andan ensuing time point T_(current).
 94. A method according to claim 93,wherein the signal delivered to the GD_(n) is computed based on the sumof the output of the controller and a volume of G_(n) that must be addedto G₀ ^(P) (G_(n) ^(P)) so that the incremental volume of DA_(n) in thecombined volume of G₀ ^(P) and G_(n) ^(P) equals DA_(n) ^(T).
 95. Amethod according to claim 93, wherein the G₀ ^(P) is equated with theincremental volume of G₀ delivered in the ΔT beginning at T_(current−1)and ending at the respective T_(current).
 96. A method according toclaim 93, wherein the G₀ ^(P) is equated with one of an average and aweighted average of the incremental volumes of G₀ delivered in aplurality of time intervals of interest within T_(variable).
 97. Amethod according to claim 92, wherein the T_(variable) corresponding toa respective T_(current) is selectable based on volumetric dimension ofone of CVG_(n), CVG_(Dan), CVG₀, and CVG_(R), and a set of time pointscorresponding to at least part of at least one inspiratory cycle.
 98. Amethod according to claim 89, wherein the method is implemented by usinga processor operatively associated with a controller (VC_(n)) forcontrolling a gas delivery device (GD_(n)), which obtains input of atleast one of CVG_(n), CVG_(DAn), and at least one of CVG₀, and CVG_(R)from a volume sensor and input of concentrations of DA_(n) in G_(n)applicable to any respective T_(current) from a gas analyzer.
 99. Amethod according to claim 98, wherein the functions of the processor andthe controller (VC_(n)) are carried out by at least one of amicroprocessor and a microcontroller.